Long chain carboxylic acid imide ester

ABSTRACT

Provided is a long chain carboxylic acid imide ester (I) represented by the following general formula (I) wherein W is a divalent long chain hydrocarbon group which may optionally be interrupted by one or more groups each independently selected from the group consisting of an oxygen, atom, a sulfur atom, and a group of -N(R1)- (R1 being a lower alkyl group) and X represents a divalent hydrocarbon group which may optionally be substituted, or salt thereof. The above long chain carboxylic acid imide ester or its salts is useful for modifying enzymes or proteins having biological activities to give their derivatives which have, while retaining most of the original biological activities, an extremely prolonged plasma half-life as compared with the proteins and have no antigenecities and can be administered to animals.

This application is a divisional of application Ser. No. 07/872,534,filed Apr. 23, 1992, now U.S. Pat. No. 5,336,782.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to long chain carboxylic acid imide estersor their salts. The long chain carboxylic acid imide esters or theirsalts are useful for modifying enzymes or proteins (hereinafter enzymesand proteins are referred to simply as "proteins") having biologicalactivities, to give their derivatives which have, while retaining mostof the original biological activities, an extremely prolonged plasmahalf-life as compared with the proteins and no antigenecities and can beadministered to animals.

2. Description of the Prior Art

A number of attempts have been made to improve proteins with variousmodifiers. Polyethylene glycol (hereinafter referred to as "PEG") is oneof those modifiers which have been studied most actively in recentyears. PEG is being used for modifying, for example, anticancer agentssuch as asparaginase, arginase and interleukin-2 (hereinafter referredto as "IL-2"), thrombolytic agents such as urokinase, streptokinase,tissue plasminogen activator (hereinafter referred to as "TPA"),treating agents for enzyme deficiency diseases, such as β-glucosidase,β-glucuronidase, α-galactosidase and adenosine deaminase, gout treatingagents such as uricase, anti-inflammatory agents or anti-ischemic agentssuch as superoxide dismutase (hereinafter sometimes referred to as"SOD"), diabetes treating agent of insulin, and hyperbilirubinemiatreating agent or bilirubin oxidase. In more recent years, an attemptwas made to modify granulocyte colony-stimulating factor (hereinafterreferred to as "G-CSF"), which is one of hematopoietic factors, with PEGto prolong its plasma half-life and to use it for treating hematopoieticdisorder and like purposes [Japanese Patent Application Laid-open No.316400/1989 and International Laid-open No. WO90/06952]. There have beenstudied and used modifiers other than PEG, and there examples arenatural polymers, such as serum albumin and dextran, and polyasparticacid, partially half-esterified styrene-maleic anhydride copolymer(hereinafter referred to as "SMA") and reactable derivatives of longchain fatty acids ["Tanpakushitsu Haiburido" ("Protein Hybrids"),Chapters 1, 2, 3 and 6, published by Kyoritsu Shuppan Co. on Apr. 1,1987, "Zoku Tanpakushitsu Haiburido" ("Protein Hybrids; a 2nd series"),Chapters 3, 4 and 6, published by Kyoritsu Shuppan Co. on May 20, 1988and "SOD No Shinchiken" ("New Findings on SOD"), p. 107, published byNihon Akuseru Shupuringa Co. on Dec. 20, 1990.]

SOD modified with serum albumin has antigenicity [Agents and Actions,10, 231 (1980)]. Although the structures of other modifiers includingdextran, PEG, polyaspartic acid and SMA can be specified from theviewpoint of polymer chemistry, they have a certain distribution intheir molecular weights. The molecular weights of proteins modified withthese polymers are therefore not constant, which is a problem inpractical applications in view of the current situation in which thecompound to be used as a medicinally active ingredient should preferablyhave a single chemical structure.

Accordingly, an object of the present invention is to provide a novellong chain carboxylic acid imide ester or its salts that can modifyproteins to obtain protein derivatives having significantly prolongedplasma half-life as compared with that of unmodified proteins and noantigenicity and can be administered to animals.

This order was well as other objects and advantages of the presentinvention will be apparent to those skilled in the art from thefollowing detailed description.

SUMMARY OF THE INVENTION

The present invention provides a long chain carboxylic acid imide ester(hereafter referred to as "long chain carboxylic acid imide ester (I)")represented by the following general formula (I) ##STR2## wherein W is adivalent long chain hydrocarbon group which may optionally beinterrupted by one or more groups each independently selected from thegroup consisting of an oxygen atom, a sulfur atom and a group of--N(R¹)--(R¹ being a lower alkyl group) and X represents a divalenthydrocarbon residue which may optionally be substituted, or saltsthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same become betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows schematic electrophorograms of the reaction mixtures,wherein (a) and (b) are that of the SOD used in Reference Example 1 andthat of SOD derivative-C obtained in Reference Example 1, respectively;

FIG. 2 shows an IR-spectrum of the SOD derivative-C obtained inReference Example 1;

FIG. 3 shows schematic electrophorograms of (a) the SOD used inReference Example 2 and (b) the SOD derivative obtained in ReferenceExample 2;

FIG. 4 shows an IR-spectrum of the SOD derivative obtained in ReferenceExample 2;

FIG. 5 shows schematic electrophorograms of (a) the SOD used inReference Example 3 and (b) the SOD derivative obtained in ReferenceExample 3;

FIG. 6 shows an IR-spectrum of the SOD derivative obtained in ReferenceExample 3;

FIG. 7 shows schematic electrophorograms of (a) the NCS used inReference Example 4 and (b) the NCS derivative obtained in ReferenceExample 4;

FIG. 8 shows an IR-spectrum of the NCS derivative obtained in ReferenceExample 4;

FIG. 9 shows schematic electrophorograms of (a) the NCS used inReference Example 5 and (b) the NCS derivative obtained in ReferenceExample 5;

FIG. 10 shows an IR-spectrum of the NCS derivative obtained in ReferenceExample 5;

FIG. 11 shows the time courses of the plasma concentrations in TestExample 1, wherein (1), (2), (3) and (4) are for unmodified SOD, the SODderivatives-A, -B and -C obtained in Reference Example 1, respectively.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The divalent hydrocarbon group represented by W in the long chaincarboxylic acid imide ester (I) of the present invention preferably has8 to 28 principal chain atoms, more preferably 10 to 20 atoms, in viewof the usefulness of the long chain carboxylic acid imide ester (I) aschemical modifier for proteins.

Examples of the lower alkyl group represented by R¹ are methyl, ethyl,propyl and isopropyl.

Examples of the divalent long chain hydrocarbon group represented by Win the long chain carboxylic acid imide ester (I) are as follows.(CH₂)₁₀, (CH₂)₁₁, (CH₂)₁₂, (CH₂)₁₃, (CH₂)₁₄, (CH₂)₁₅, (CH₂)₁₆, (CH₂)₁₇,(CH₂)₁₈, (CH₂)₁₉, (CH₂)₂₀, CH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CH(CH₂)₇, (CH₂)₃CH═CH(CH₂)₇, (CH₂)₄ CH═CH(CH₂)₇, (CH₂)₅ CH═CH(CH₂)₇, (CH₂)₆ CH═CH(CH₂)₇,(CH₂)₇ CH═CH(CH₂)₇, (CH₂)₈ CH═CH(CH₂)₇, (CH₂)₉ CH═CH(CH₂)₇, (CH₂)₁₀CH═CH(CH₂)₇, (CH₂)₁₁ CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂, (CH₂)₈ CH═CH(CH₂)₂,(CH₂)₈ CH═CH(CH₂)₃, (CH₂)₈ CH═CH(CH₂)₄, (CH₂)₈ CH═CH(CH₂)₅, (CH₂)₈CH═CH(CH₂)₆, (CH₂)₈ CH═CH(CH₂)₇, (CH₂)₈ CH═CH(CH₂)₈, (CH₂)₈ CH═CH(CH₂)₉,(CH₂)₈ CH═CH(CH₂)₁₀, CH₂ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CHCH₂CH═CH(CH₂)₇, (CH₂)₃ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₄ CH═CHCH₂ CH═CH(CH₂)₇,(CH₂)₅ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₆ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₇CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₂ --O--(CH₂)₇,(CH₂)₂ --O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₉, (CH₂)₂ --O--(CH₂)₁₀, (CH₂)₂--O--(CH₂)₁₁, .[.(CH₂)₂ --O--(CH₂)₂,.]. .Iadd.(CH₂)₂ --O--(CH₂)₁₂,.Iaddend.(CH₂)₂ --O--(CH₂)₁₃, (CH₂)₂ --O--(CH₂)₁₄, (CH₂)₂ --O--(CH₂)₁₅,(CH₂)₂ --O--(CH₂)₁₆, (CH₂)₂ --O--(CH₂)₁₇, (CH₂)₄ --O--(CH₂)₅, (CH₂)₄--O--(CH₂)₆, (CH₂)₄ --O--(CH₂)₇, (CH₂)₄ --O--(CH₂)₈, (CH₂)₄ --O--(CH₂)₉,(CH₂)₄ --O--(CH₂)₁₀, (CH₂)₄ --O--(CH₂)₁₁, (CH₂)₄ --O--(CH₂)₁₂, (CH₂)₄--O--(CH₂)₁₃, (CH₂)₄ --O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₁₅, (CH₂)₆--O--(CH₂)₃, (CH₂)₆ --O--(CH₂)₄, (CH₂)₆ --O--(CH₂)₅, (CH₂)₆ --O--(CH₂)₆,(CH₂)₆ --O--(CH₂)₇, (CH₂)₆ --O--(CH₂)₈, (CH₂)₆ --O--(CH₂)₉, (CH₂)₆--O--(CH₂)₁₀, (CH₂)₆ --O--(CH₂)₁₁, (CH₂)₆ --O--(CH₂)₁₂, (CH₂)₆--O--(CH₂)₁₃, (CH₂)₈ --O--CH₂, (CH₂)₈ --O--(CH₂)₂, (CH₂)₈ --O--(CH₂)₃,(CH₂)₈ --O--(CH₂)₄, (CH₂)₈ --O--(CH₂)₅, (CH₂)₈ --O--(CH₂)₆, (CH₂)₈--O--(CH₂)₇, (CH₂)₈ --O--(CH₂)₈, (CH₂)₈ --O--(CH₂)₉, (CH₂)₈--O--(CH₂)₁₀, (CH₂)₈ --O--(CH₂)₁₁, (CH₂)₁₀ --O--CH₂, (CH₂)₁₀--O--(CH₂)₂, (CH₂)₁₀ --O--(CH₂)₃, (CH₂)₁₀ --O--(CH₂)₄, (CH₂)₁₀--O--(CH₂)₅, (CH₂)₁₀ --O--(CH₂)₆, (CH₂)₁₀ --O--(CH₂)₇, (CH₂)₁₀--O--(CH₂)₈, (CH₂)₁₀ --O--(CH₂)₉, (CH₂)₁₂ --O--CH₂, (CH₂)₁₂ --O--(CH₂)₂,(CH₂)₁₂ --O--(CH₂)₃, (CH₂)₁₂ --O--(CH₂)₄, (CH₂)₁₂ --O--(CH₂)₅, (CH₂)₁₂--O--(CH₂)₆, (CH₂)₁₂ --O--(CH₂)₇, CH₂ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₂--O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₃ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₄--O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₅ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₂--S--(CH₂)₇, (CH₂)₂ --S--(CH₂)₈, (CH₂)₂ --S--(CH₂)₉, (CH₂)₂--S--(CH₂)₁₀, (CH₂)₂ --S--(CH₂)₁₁, (CH₂)₂ --S--(CH₂)₁₂, (CH₂)₂--S--(CH₂)₁₃, (CH₂)₂ --S--(CH₂)₁₄, (CH₂)₂ --S--(CH₂)₁₅, (CH₂)₂--S--(CH₂)₁₆, (CH₂)₂ --S--(CH₂)₁₇, (CH₂)₄ --S--(CH₂)₅, (CH₂)₄--S--(CH₂)₆, (CH₂)₄ --S--(CH₂)₇, (CH₂)₄ --S--(CH₂)₈, (CH₂)₄ --S--(CH₂)₉,(CH₂)₄ --S--(CH₂)₁₀, (CH₂)₄ --S--(CH₂)₁₁, (CH₂)₄ --S--(CH₂)₁₂, (CH₂)₄--S--(CH₂)₁₃, (CH₂)₄ --S--(CH₂)₁₄, (CH₂)₄ --S--(CH₂)₁₅, (CH₂)₆--S--(CH₂)₃, (CH₂)₆ --S--(CH₂)₄, (CH₂)₆ --S--(CH₂)₅, (CH₂)₆ --S--(CH₂)₆,(CH₂)₆ --S--(CH₂)₇, (CH₂)₆ --S--(CH₂)₈, (CH₂)₆ --S--(CH₂)₉, (CH₂)₆--S--(CH₂)₁₀, (CH₂)₆ --S--(CH₂)₁₁, (CH₂)₆ --S--(CH₂)₁₂, (CH₂)₆--S--(CH₂)₁₃, (CH₂)₈ --S--CH₂, (CH₂)₈ --S--(CH₂)₂, (CH₂)₈ --S--(CH₂)₃,(CH₂)₈ --S--(CH₂)₄, (CH₂)₈ --S--(CH₂)₅, (CH₂)₈ --S--(CH₂)₆, (CH₂)₈--S--(CH₂)₇, (CH₂)₈ --S--(CH₂)₈, (CH₂)₈ --S--(CH₂)₉, (CH₂)₈--S--(CH₂)₁₀, (CH₂)₈ --S--(CH₂)₁₁, (CH₂)₁₀ --S--CH₂, (CH₂)₁₀--S--(CH₂)₂, (CH₂)₁₀ --S--(CH₂)₃, (CH₂)₁₀ --S--(CH₂)₄, (CH₂)₁₀--S--(CH₂)₅, (CH₂)₁₀ --S--(CH₂)₆, (CH₂)₁₀ --S--(CH₂)₇, (CH₂)₁₀--S--(CH₂)₈, (CH₂)₁₀ --S--(CH₂)₉, (CH₂)₁₂ --S--CH₂, (CH₂)₁₂ --S--(CH₂)₂,(CH₂)₁₂ --S--(CH₂)₃, (CH₂)₁₂ --S--(CH₂)₄, (CH₂)₁₂ --S--(CH₂)₅, (CH₂)₁₂--S--(CH₂)₆, (CH₂)₁₂ --S--(CH₂)₇, (CH₂)₂ --N(CH₃)--(CH₂)₇, (CH₂)₂--N(CH₃)--(CH₂)₈, (CH₂)₂ --N(CH₃)--(CH₂)₉, (CH₂)₂ --N(CH₃)--(CH₂)₁₀,(CH₂)₂ --N(CH₃)--(CH₂)₁₁, (CH₂)₂ --N(CH₃)--(CH₂)₁₂, (CH₂)₂--N(CH₃)--(CH₂)₁₃, (CH₂)₂ --N(CH₃)--(CH₂)₁₄, (CH₂)₂ --N(CH₃)--(CH₂)₁₅,(CH₂)₂ --N(CH₃)--(CH₂)₁₆, (CH₂)₂ --N(CH₃)--(CH₂)₁₇, (CH₂)₄--N(CH₃)--(CH₂)₅, (CH₂)₄ --N(CH₃)--(CH₂)₆, (CH₂)₄ --N(CH₃)--(CH₂)₇,(CH₂)₄ --N(CH₃)--(CH₂)₈, (CH₂)₄ --N(CH₃)--(CH₂)₉, (CH₂)₄--N(CH₃)--(CH₂)₁₀, (CH₂)₄ --N(CH₃)--(CH₂)₁₁, (CH₂)₄ --N(CH₃)--(CH₂)₁₂,(CH₂)₄ --N(CH₃)--(CH₂)₁₃, (CH₂)₄ --N(CH₃)--(CH₂)₁₄, (CH₂)₄--N(CH₃)--(CH₂)₁₅, (CH₂)₆ --N(CH₃)--(CH₂)₃, (CH₂)₆ --N(CH₃)--(CH₂)₄,(CH₂)₆ --N(CH₃)--(CH₂)₅, (CH₂)₆ --N(CH₃)--(CH₂)₆, (CH₂)₆--N(CH₃)--(CH₂)₇, (CH₂)₆ --N(CH₃)--(CH₂)₈, (CH₂)₆ --N(CH₃)--(CH₂)₉,(CH₂)₆ --N(CH₃)--(CH₂)₁₀, (CH₂)₆ --N(CH₃)--(CH₂)₁₁, (CH₂)₆--N(CH₃)--(CH₂)₁₂, (CH₂)₆ --N(CH₃)--(CH₂)₁₃, (CH₂)₂ --N(C₂ H₅)--(CH₂)₇,(CH₂)₂ --N(C₂ H₅)--(CH₂)₈, (CH₂)₂ --N(C₂ H₅)--(CH₂)₉, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₀, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₂,(CH₂)₂ --N(C₂ H₅)--(CH₂)₁₃, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₄, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₅, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₆, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₇,(CH₂)₄ --N(C₂ H₅)--(CH₂)₅, (CH₂)₄ --N(C₂ H₅)--(CH₂)₆, (CH₂)₄ --N(C₂H₅)--(CH₂)₇, (CH₂)₄ --N(C₂ H₅)--(CH₂)₈, (CH₂)₄ --N(C₂ H₅)--(CH₂)₉,(CH₂)₄ --N(C₂ H₅)--(CH₂)₁₀, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₄ --N(C₂H₅)--(CH₂)₁₂, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₃, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₄,(CH₂)₄ --N(C₂ H₅)--(CH₂)₁₅, (CH₂)₆ --N(C₂ H₅)--(CH₂)₃, (CH₂)₆ --N(C₂H₅)--(CH₂)₄, (CH₂)₆ --N(C₂ H₅)--(CH₂)₅, (CH₂)₆ --N(C₂ H₅)--(CH₂)₆,(CH₂)₆ --N(C₂ H₅)--(CH₂)₇, (CH₂)₆ --N(C₂ H₅)--(CH₂)₈, (CH₂)₆ --N(C₂H₅)--(CH₂)₉, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₀, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₁,(CH₂)₆ --N(C₂ H₅)--(CH₂)₁₂, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₃, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₅, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₇, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₉, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₀, .[.(CH₂)₂ --o--(CH₂)₂ --O--(CH₂)₁₁,.]..Iadd.(CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₁, .Iaddend.(CH₂)₂ --O--(CH₂)₂--O--(CH₂)₁₂, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₃, (CH₂)₂ --O--(CH₂)₂--O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₂, (CH₂)₄ --O--(CH₂)₂--O--(CH₂)₃, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₄ --O--(CH₂)₂--O--(CH₂)₅, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₄ --O--(CH₂)₂--O--(CH₂)₇, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₄ --O--(CH₂)₂--O--(CH₂)₉, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₄ --O--(CH₂)₂--O--(CH₂)₁₁, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₂, (CH₂)₂ --S--S--(CH₂)₇,(CH₂)₂ --S--S--(CH₂)₉, (CH₂)₂ --S--S--(CH₂)₁₁, (CH₂)₂ --S--S--(CH₂)₁₃,(CH₂)₂ --S--S--(CH₂)₁₅, (CH₂)₄ --S--S--(CH₂)₅, (CH₂)₄ --S--S--(CH₂)₇,(CH₂)₄ --S--S--(CH₂)₉, (CH₂)₄ --S--S--(CH₂)₁₁, (CH₂)₄ --S--S--(CH₂)₁₃,(CH₂)₆ --S--S--(CH₂)₃, (CH₂)₆ --S--S--(CH₂)₅, (CH₂)₆ --S--S--(CH₂)₇,(CH₂)₆ --S--S--(CH₂)₉, (CH₂)₆ --S--S--(CH₂)₁₁, (CH₂)₈ --S--S--(CH₂,(CH₂)₈ --S--S--(CH₂)₃, (CH₂)₈ --S--S--(CH₂)₅, (CH₂)₈ --S--S--(CH₂)₇,(CH₂)₈ --S--S--(CH₂)₉.

The imide moiety of the long chain carboxylic acid imide ester (I) maybe of any structure in view of the usefulness of the long chaincarboxylic acid imide ester (I) as chemical modifiers for proteins. Thegroups represented by X in the above general formula (I) therefore doesnot constitute an essential part of the invention and may be anydivalent hydrocarbon residue without limitation.

It is however desirable, in view of availability of starting materialsand easiness of synthesis, to use as the imide part of the long chaincarboxylic acid imide ester (I)

an imide part represented by the following general formula (A)(hereinafter referred to as "imide part A") ##STR3## wherein R², R³, R⁴and R⁵, which may be the same or different, each represents a hydrogenatom, an alkyl group, an aryl groups, an aralkyl group, an --SO₃ Hgroup, a group represented by --OR⁶ wherein R⁶ represents a hydrogenatom, an alkyl group, an aryl group, an aralkyl group or an acyl group,a group represented by --NR⁷ R⁸ wherein R⁷ and R⁸, which may be the sameor different, each represents an alkyl group, an aryl group, an aralkylgroup or an acyl group or a group represented by --CO₂ R⁹ wherein R⁹represents a hydrogen atom, an alkyl group, an aryl group or an aralkylgroup, R², R³, R⁴ and R⁵ may, in combination with the carbon atoms towhich they bond, form a ring which may be substituted, R² and R³ and/orR⁴ and R⁵, in combination, may represent a methylene group which may besubstituted; or

an imide part represented by the following general formula (B) ##STR4##wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, which may be the same ordifferent, each represents a hydrogen atom, an alkyl group, an arylgroup, an aralkyl group, an --SO₃ H group, a group represented by theformula --OR⁶ wherein R⁶ is as defined above, a group represented by theformula --NR⁷ R⁸ wherein R⁷ and R⁸ are as defined above or a grouprepresented by the formula --CO₂ R⁹ wherein R⁹ is as defined above; ofwhich the imide part A is more preferred.

Examples of the alkyl group that may be represented by R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ in the above formulas(A) and (B) are methyl, ethyl, propyl, isopropyl and octadecyl. Examplesof the aryl group are phenyl and p-bromophenyl. Examples of the aralkylgroup are benzyl and p-methoxybenzyl. Examples of the acyl group thatmay be represented by R⁶, R⁷ and R⁸ are acetyl and benzoyl.

Examples of the group represented by the formula --OR⁶ are hydroxylgroup, alkoxy groups such as methoxy, ethoxy, propoxy and isopropoxy,aryloxy groups such as phenoxy and p-bromophenoxy and aralkyloxy groupssuch as benzyloxy and p-methoxybenzyloxy. Examples of the grouprepresented by the formula --NR⁷ R⁸ are substituted amino groups such asdimethylamino and diethylamino and N-substituted acylamido groups suchas N-methylacetamido and N-methylbenzamido. Examples of the grouprepresented by the formula --CO₂ R⁹ are carboxyl group, alkoxycarbonylgroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarboxyl andisopropoxycarbonyl and aryloxycarbonyl groups such as phenoxycarbonyland p-bromophenoxycarbonyl.

In the above formula (A), where R², R³, R⁴ and R⁵ form, in combinationwith the carbon atoms to which they bond, a saturated or unsaturatedring which may be substituted, examples of the saturated or unsaturatedring which may be substituted are those having as basic skeleton benzenering, cyclohexane ring and cyclopentane ring, as well asbicyclo-[2,2,1]heptane skeleton, bicyclo[2,2,1] hepta-2-en skeleton,7-oxabicyclo[2,2,1]heptane skeleton and 7-oxabicyclo[2,2,1]-hepta-2-enskeleton.

Concrete examples of the imide part A having these saturated orunsaturated ring are as follows. ##STR5##

Where R² and R³ and/or R⁴ and R⁵, in combination, each form a methylenegroup which may be substituted, examples of the methylene group whichmay be substituted are methylene group and isopropylidene group.

Concrete examples of the imide part A having the methylene group whichmay be substituted are shown below. ##STR6##

Examples of the salt of the long chain carboxylic acid imide ester (I)are salts with alkali metals, e.g. lithium, sodium and potassium andsalts with alkali earth metals, e.g. magnesium and calcium. The saltsare formed at the long chain carboxylic acid part and/or imide part ofthe long chain carboxylic acid imide ester (I).

The long chain carboxylic acid imide ester (I) is produced by subjectinga long chain dicarboxylic acid (hereinafter referred to as "long chaindicarboxylic acid (II)") represented by the general formula (II)

    HO.sub.2 C--W--CO.sub.2 H                                  (II)

wherein W is as defined above, to dehydration condensation with anequimolar amount of an N-hydroxyimide (hereinafter referred to as"N-hydroximide (III)") represented by the following general formula(III)). ##STR7## wherein X is as defined before, in the presence ofdicyclohexylcarbodiimide (hereinafter referred to as "DCC").

The long chain carboxylic acid imide ester (I) may, except for the casewhere R² and R³ and/or R⁴ and R⁵, in combination, each form a methylenegroup which may be substituted, also be produced by the following steps.

(1) A long chain carboxylic acid (II) is subjected to dehydrationcondensation with an equimolar amount of benzyl alcohol in the presenceof DCC, to yield a long chain dicarboxylic acid monobenzyl ester(hereinafter referred to as "long chain dicarboxylic acid monobenzylester (IV)") represented by the following general formula (IV) ##STR8##wherein W is as defined above. (2) The long chain dicarboxylic acidmonobenzyl ester (IV) is reacted with N-hydroximide (III) in the usualmanner to give a long chain dicarboxylic acid monobenzyl monoimide ester(hereinafter referred to as "long chain dicarboxylic acid diester (V)")represented by the following general formula (V) ##STR9## wherein W andX are as defined above. (3) The benzyl ester part of the long chaindicarboxylic acid diester (V) is removed by hydrogenolysis in the usualmanner, to obtain the desired compound.

The salt of the long chain carboxylic acid imide ester (I) issynthesized by the usual salt formation process. Where the imide part ofthe long chain carboxylic acid imide ester (I) forms the salt, the saltmay be synthesized by conducting similar reactions to the above with asalt of N-hydroximide (III) as a starting material.

The long chain carboxylic acid imide ester (I) or its salts of thepresent invention (hereinafter referred to as "long chain carboxylicacid imide ester derivative") is useful as chemical modifier ofproteins.

The long chain carboxylic acid imide ester derivative is reacted with aprotein in an aqueous solution at a pH of 6 to 10 to yield a proteinderivative represented by the following formula

    [protein][Z]n

wherein [protein] represents a protein having n amino residues eachderivable from amino group by removal of one of its hydrogen atoms,instead of amino groups, [Z] is a residue (hereinafter referred to as"long chain carboxylic acid residue") represented by the followinggeneral formula ##STR10## wherein W is as defined above, and derivablefrom a long chain dicarboxylic acid (II) by removal of a hydroxyl groupfrom one of its carboxyl groups, and n represents an average of thenumber of amide bonds between [Z] and [protein], which is in a range of1 to 8.

The reaction of the long chain carboxylic acid imide ester derivativewith a protein is, although details differ more or less depending on thetype of the protein, generally conducted by dissolving the protein in anaqueous solution of a salt such as sodium carbonate, sodiumhydrogencarbonate, sodium acetate or sodium phosphate, and adding to theobtained solution the long chain carboxylic acid imide ester derivativein the powder form or in the form of a solution in an organic solventsuch as dimethyl sulfoxide. It is necessary to maintain the pH of thesolution within a range of 6 to 10 during the reaction. If the pH islower than 6, the solubility of the long chain carboxylic acid imideester derivative will decrease, whereby the reaction hardly proceeds. Ifthe pH is higher than 10, the protein will be inactivated in most casesso that it becomes difficult to effectively obtain the proteinderivatives of the present invention. The reaction temperature ispreferably not more than the denaturation temperature of the protein andgenerally about 3° to 50° C., more preferably about 3° to 40° C. Thereaction time is, while varying depending on the reaction temperatureand the way how the long chain carboxylic acid imide ester derivative isadded, generally in a range of about 10 to 30 days. The amount used ofthe long chain carboxylic acid imide ester derivative is about 1 to 100moles based on 1 mole of the protein. Where SOD is used as protein, theamount of the long chain carboxylic acid imide ester derivative ispreferably about 2 to 50 moles based on 1 mole of SOD. The amount usedcan control the number of molecules of the long chain carboxylic acidresidue bounded to the protein.

The reaction mixture thus obtained contains the resulting proteinderivative, unreacted protein, the long chain carboxylic acid imideester derivative and the like. The reaction mixture is filtered and thefiltrate is then subjected to gel filtration. The obtained eluatecontaining the protein derivative is as required subjected tohydrophobic chromatography, ion-exchange chromatography or the like andconcentrated by ultrafiltration, and is subjected to lyophilization, togive the protein derivative in the solid form.

In the above reaction, the amino groups of the protein react with thelong chain carboxylic acid imide ester derivative, to form the proteinderivative.

The protein derivative obtained by the above reaction is a mixture ofthose obtained by reacting the protein with one or more molecules of thelong chain carboxylic acid imide ester derivative, so that the numbersof the long chain carboxylic acid residue contained in 1 molecule of theprotein derivative are not the same. In the above general formularepresenting a protein derivative, n therefore means an average value ofthe numbers of the long chain carboxylic acid residues bonded to 1molecule of the protein. If however a protein derivative in which thenumbers of the long chain carboxylic acid residues bonded to 1 moleculeof the protein are the same is desired, it can be obtained by subjectingthe protein derivative obtained by the above process further to gelfiltration, ion-exchange chromatography or like processes. In the abovereaction and processes after the reaction, the carboxyl groups presentin the protein derivative may form alkali metal salts or ammonium salts.The protein derivative containing carboxyl groups in salt form can alsobe used as effective ingredient of medicines without any problem.

The protein derivative contain 1 to 8 long chain carboxylic acidresidues bonded to 1 molecule of the protein and has a significantlyprolonged plasma half-life as compared to the unmodified protein. Amongprotein derivatives, neocarzinostatin (hereinafter referred to as "NCS")derivative is, in view of prolongation of plasma half-life anddeterminability of chemical structure, desirably modified with the longchain carboxylic acid imide ester derivative at its 1-position alanineand at its 20-position lysine.

Examples of the protein used as the starting material for the abovereaction are as follows.

Asparaginase, arginase, interleukin-1, IL-2, interleukin-3,interleukin-4, interleukin-5, interleukin-6, interleukin-7,interleukin-8, urokinase, prourokinase, streptokinase, TPA,β-glucosidase, β-glucuronidase, α-galactosidase, adenosine deaminase,uricase, SOD, insulin, bilirubin oxidase, G-CSF, granulocyte macrophagecolony-stimulating factor, macrophage colony-stimulating factor, NCS,catalase, elastase, erythropoietin, interferon-α, interferon-β,interferon-γ, tumor necrosis factor-α, tumor necrosis factor-β, nervegrowth factor, epidermal growth factor, ovalbumin, platelet derivedgrowth factor, thrombomodulin, α1-antitrypsin, bone morphogeneticprotein, cartilage derived factor, fibroblast growth factor, growthhormone, transforming growth factor-β(TGF-β), blood coagulation factorIX, protein C, protein S, insulin-like growth factor, calcitonin,somatostatin, tissue inhibitor of metalloproteinase (TIMP), atrialnatriuretic hormone, CD-4 protein, cystatin, calpastatin, urinastatinand parathyroid hormone.

The long chain carboxylic acid imide ester derivative of the presentinvention has a fatty acid portion. The protein derivative modified bysuch long chain carboxylic acid imide ester therefore is capable ofreversibly binding plasma protein and biological membrane, whereby ithas prolonged plasma half-life and the feature of good delivery toorgans.

It is preferable that, in the long chain carboxylic acid imide ester,the long chain hydrocarbon residue represented by W have 8 to 28, morepreferably 10 to 20 principal chain atoms. Where SOD is modified, it isparticularly preferred that the number of principal chain atoms of thelong chain hydrocarbon residue represented by W be 10 to 15. If a longchain carboxylic acid imide ester with the number of principal chainatoms being less than 8 is reacted with protien, the resulting proteinderivative will have poor affinity to plasma protein. If the number islarger than 28, the long chain carboxylic acid imide ester will havepoor solubility in an aqueous solution with a pH of 6 to 10, whereby itbecomes difficult to bond such long chain carboxylic acid imide ester toprotein.

The protein derivative effectively exhibits the pharmacological effectinherent to the unmodified protein. For example, SOD derivative has, asis apparent from the results obtained in Test Examples 2 which will bedescribed later herein, excellent anti-ulcer activity, and also haspharmacological activities such as anti-inflammatory, anti-ischemic andcerebral edema-preventing activities. NCS derivative has excellentanti-cancer activity.

Toxicological studies have shown the low toxicity of the proteinderivatives.

The above results show that the protein derivatives are effective fortreating or preventing various diseases corresponding to thepharmacological activities known to be inherent to the unmodifiedprotein.

SOD derivatives are effective for diseases caused by active oxygenspecies, and can be used in particular as anti-inflammatory agents,anti-ulcer agents, anti-ischemic agents, cerebral edema-preventingagents, anti-paraquat intoxication agents, etc. and are also useful asdrugs to alleviate various side effects induced by anti-cancer agents,as caused by active oxygen species. Further, the SOD derivatives areuseful as therapeutic agents for treating dermal diseases such as burn,trauma and various dermatides. The SOD derivatives more effectivelyretain the pharmacological activities inherent to unmodified SOD[Saishin Igaku, 39, No. 2, 339 (1984); Igaku to Yakugaku, 14, No. 1, 55(1985); Jikken Igaku, 4, No. 1 (1986) "Tokushuh: Seitainai FuriiRajikaru to Shikkan" (Special Number: Free Radicals and Diseases);Fragrance Journal, 79, 89 (1986)]. Moreover, the SOD derivatives havepharmacological activities against those diseases caused by activeoxygen species and those against which unmodified SOD shows nopharmacological activities.

NCS derivatives are useful as anti-cancer agents.

The dosage of the protein derivative depends on the kind of disease,severity of the disease, patient's tolerance and other factors. Forexample, the usual daily dosage of SOD derivative for adult humans is0.1 to 500 mg and preferably 0.5 to 100 mg. The dosage of NCS derivativevaries depending on the method of administration, malignancyand type ofthe cancer, patient's condition of disease and general observation,severity of the cancer and the like, but is generally 0.1 to 100 mg foradult human and preferably 0.1 to 10 mg. The dosage is appropriatelyadministered either in a single dose or in a few divided doses. Uponadministration various dosage forms may be taken suitable for therespective routes of administration. The NCS derivative can beadministered directly to local intra-tissue such as originally developedpart of cancer or the part where an cancer has been enucleated bysurgery, or administered intracutaneously, subcutaneously,intramascularly, intravenously, intraarticularly, orally or the like, orby external administration such as external application, spraying,suppository or by insertion intourinary bladder.

The protein derivative can be formulated and prepared by the establishedpharmaceutical procedures into pharmaceutical compositions. Suchpharmaceutical compositions can be manufactured using pharmaceuticallyacceptable carriers, vehicles and other auxiliary substances which arecommonly used in pharmaceutical practice.

When such pharmaceutical compositions are intended for oraladministration, they are preferably provided in dosage forms suitablefor absorption from the gastrointestinal tract. Tablets and capsuleswhich are unit dosage forms for oral administration may contain binderssuch as syrup, gum arabic, gelatin, sorbitol, gum tragacanth andpolyvinylpyrrolidione; excipients such as lactose, corn starch, calciumphosphate, sorbitol and glycine; lubricants such as magnesium stearate,talc, polyethylene glycol and silica; disintegrators such as potatostarch; pharmaceutically acceptable wetting agents such as sodiumlaurylsulfate and so on. The tablets may be coated in the well-knownmanner. Liquid preparation for oral administration may be aqueous oroily suspensions, solutions, syrups, elixirs and so on, or may belyophilisates which are extemporaneously reconstituted with water orother suitable vehicles before use. Such liquid preparations may containthe usual additives inclusive of suspending agents such as sorbitolsyrup, methylcellulose, glucose/sucrose syrup, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andhydrogenated edible oils and fats; emulsifiers such as lecithin,sorbitan monooleate and gum arabic; non-aqueous vehicles such as almondoil, fractionated coconut oil, oleaginous esters, propylene glycol andethanol; preservatives such as methyl p-hydroxybenzoate, propylp-hydroxybenzoate and sorbic acid; and so forth.

For preparing injections, the protein derivative is dissolved in ansuitable solvent such as physiological saline and glucose solution forinjection; and the SOD derivative concentration is adjusted to 2 to 20mg per 2 to 10 ml of solvent in a conventional manner to give injectionsfor subcutaneous, intramuscular or intravenous administration. Inpreparing the above injections, pH-adjusting agents, buffers,stabilizers, preservatives, solubilizer and so forth may be added to theaqueous solution, if necessary.

The above-mentioned pharmaceutical composition can contain the proteinderivative in a concentration selected according to the form thereof andother factors, generally in a concentration of about 0.01 to 50% byweight, preferably about 0.1 to 20% by weight.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

In the Examples that follow, ¹ H-NMR was measured usingtetramethylsilane as internal standard. IR absorption spectrum wasmeasured by KBr disk method.

EXAMPLES Example 1 Synthesis of N-(13-carboxytridecanoyloxy)succinimide

In 15 ml of anhydrous tetrahydrofuran 1,14-tetradecanedioic acid (1.0 g,3.87 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxysuccinimide (445 mg, 3.87 mmoles) in 5 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(3.1 mg, 0.02 mmole) and the mixture was stirred for 30 minutes. To themixture was added a solution of DCC (799 mg, 3.87 mmoles) in 5 ml ofanhydrous tetrahydrofuran and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was separated andpurified by silica gel chromatography [eluent: mixture of benzene andchloroform (volume ratio): 1:3], to giveN-(13-carboxytridecanoyloxy)succinimide (510 mg, 37%) having thefollowing properties.

m.p. 116°-118° C.

FD-MS (m/z): [M+H]⁺ 356

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.47 (m, 16H), 1.63 (m, 2H) 1.74 (m,2H), 2.35 (t, 2H), 2.57 (t, 2H), 2.84 (s, 4H), 7.85-10.50 (br, 1H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 2 Synthesis of N-(15-carboxypentadecanoyloxy)succinimide

In 30 ml of anhydrous tetrahydrofuran 1,16-hexadecanedioic acid (1.0 g,3.49 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxysuccinimide (402 mg, 3.49 mmoles) in 10 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(2.8 mg, 0.018 mmole) and the mixture was stirred for 30 minutes. To themixture was added a solution of DCC (720 mg, 3.49 mmoles) in 10 ml ofanhydrous tetrahydrofuran and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was separated andpurified by silica gel chromatography [eluent: mixture of benzene andchloroform (volume ratio): 1:3], to giveN-(15-carboxypentadecanoyloxy)succinimide (429 mg, 32%) having thefollowing properties.

m.p. 118.5°-121° C.

FD-MS (m/z): [M+H]⁺ 384

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.45 (m, 20H), 1.62 (m, 2H) 1.74 (m,2H), 2.34 (t, 2H), 2.60 (t, 2H), 2.84 (s, 4H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 3 Synthesis of N-(17-carboxyheptadecanoyloxy)succinimide

In 30 ml of anhydrous tetrahydrofuran 1,18-octadecanedioic acid (1.0 g,3.18 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxysuccinimide (366 mg, 3.18 mmoles) in 10 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(2.5 mg, 0.016 mmole) and the mixture was stirred for 30 minutes. To themixture was added a solution of DCC (656 mg, 3.18 mmoles) in 10 ml ofanhydrous tetrahydrofuran and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was separated andpurified by silica gel chromatography [eluent: mixture of benzene andchloroform (volume ratio): 1:3.5], to giveN-(17-carboxyheptadecanoyloxy)succinimide (480 mg, 37%) having thefollowing properties.

m.p. 120°-122.5° C.

FD-MS (m/z): [M+H]⁺ 412

¹ H-NMR (CDCl₃, 270 MHz): δ 1.13-1.47 (m, 24H), 1.63 (m, 2H) 1.75 (m,2H), 2.34 (t, 2H), 2.60 (t, 2H), 2.84 (s, 4H), 5.0-7.0 (br, 1H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 4 Synthesis of N-(9-carboxynonadecanoyloxy)succinimide

In 50 ml of anhydrous tetrahydrofuran 1,20-eicosanedioic acid (1.0 g,2.92 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxysuccinimide (336 mg, 2.92 mmoles) in 10 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(2.3 mg, 0.015 mmole) and the mixture was stirred for 30 minutes. To themixture was added a solution of DCC (602 mg, 2.92 mmoles) in 10 ml ofanhydrous tetrahydrofuran and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was separated andpurified by silica gel chromatography [eluent: mixture of benzene andchloroform (volume ratio): 1:3.5], to giveN-(19-carboxynonadecanoyloxy)succinimide (420 mg, 33%) having thefollowing properties.

m.p. 121.5°-124° C.

FD-MS (m/z): [M+H]⁺ 440

¹ N-NMR (CDCl₃, 270 MHz): δ 1.14-1.45 (m, 28H), 1.63 (m, 2H), 1.74 (m,2H), 2.35 (t, 2H), 2.60 (t, 2H), 2.84 (s, 4H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 5 Synthesis of N-(21-carboxyheneicosanoyloxy)succinimide

In 70 ml of anhydrous tetrahydrofuran 1,22-docosanedioic acid (1.0 g,2.70 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxysuccinimide (311 mg, 2.70 mmoles) in 10 ml ofanhydrous tetrahydorfuran and N,N-dimethylaminopyridine hydrochloride(2.1 mg, 0.014 mmole) and the mixture was stirred for 30 minutes. To themixture was added a solution of DCC (602 mg, 2.70 mmoles) in 10 ml ofanhydrous tetrahydrofuran and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was separated andpurified by silica gel chromatography [eluent: mixture of benzene andchloroform (volume ratio): 1:3.5], to giveN-(21-carboxyheneicosanoyloxy)succinimide (440 mg, 35%) having thefollowing properties.

m.p. 122°-124.5° C.

FD-MS (m/z): [M+H]⁺ 468

¹ H-NMR (CDCl₃, 270 MHz): δ 1.12-1.43 (m, 16H), 1.63 (m, 2H), 1.74 (m,2H), 2.34 (t, 2H), 2.60 (t, 2H), 2.84 (s, 4H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 6 (a) Synthesis of 1,14-tetradecanedioic acid monobenzyl ester

In 80 ml of anhydrous tetrahydrofuran 1,14-tetradecanedioic acid (5.0 g,19.4 mmoles) was dissolved. To the obtained solution, were added asolution of benzyl alcohol (2.1 g, 19.4 mmoles) in 10 ml oftetrahydrofuran and N,N-dimethylaminopyridine hydrochloride (15 mg, 0.1mmole) and mixture was stirred fo 30 minutes. To the mixture was added asolution of DCC (4.0 g, 19.4 mmoles) in 10 ml of anhydroustetrahydrofuran and the resulting mixture was stirred at a roomtemperature for 20 hours. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasseparated and purified by silica gel chromatography [eluent: mixture ofhexane and diethyl ether (volume ratio): 2:1], to give1,14-tetradecanedioic acid monobenzyl ester (2.42 g, 38%) having thefollowing properties.

m.p. 73.5°-74° C.

¹ H-NMR (CDCl₃, 270 MHz): δ 1.17-1.40 (m, 16H), 1.50-1.70 (m, 4H),2.23-2.39 (m, 4H), 5.11 (s, 2H), 7.32 (m, 5H), 7.40-9.35 (br, 1H).

(b) Synthesis of N-(13-benzyloxycarbonyltridecanoyloxy)succinimide

In 30 ml of tetrahydrofuran 1,14-tetradecanedioic acid monobenzyl ester(2.4 g, 6.89 mmoles) was dissolved. To the obtained solution, were addeda solution of N-hydroxysuccinimide (793 mg, 6.89 mmoles) in 15 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(3.3 mg, 0.02 mmole) and the mixture was stirred for 30 minutes at aroom temperature. To the mixture was added a solution of DCC (1.42 g,6.89 mmoles) in 15 ml of tetrahydrofuran and the resulting mixture wasstirred at a room temperature for 15 hours. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was separated and purified by silica gel chromatography [eluent:mixture of hexane and ethyl acetate (volume ratio): 2:1], to giveN-(13-benzyloxycarbonyltridecanoyloxy)succinimide (2.31 mg, 75%) havingthe following properties.

m.p. 61.5°-62.5° C.

¹ H-NMR (CDCl₃, 270 MHz): δ 1.05-1.46 (m, 16H), 1.63 (m, 2H) 1.72 (m,2H), 2.33 (t, 2H), 2.58 (t, 2H), 2.79 (s, 4H), 5.11 (s, 2H), 7.33 (m,5H).

(c) Synthesis of N-(13-carboxytridecanoyloxy)succinimide

In 15 ml of tetrahydrofuranN-(13-benzyloxycarbonyltridecanoyloxy)succinimide (2.28 g, 5.12 mmoles)was dissolved. To the obtained solution, were added 228 mg of 10%palladium carbon and the mixture was stirred for 15 hours under anatmosphere of hydrogen. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasrecrystallized from ethanol, to giveN-(13-carboxytridecanoyloxy)succinimide (1.71 mg, 94%) having thefollowing properties.

m.p. 116°-118° C.

FD-MS (m/z): [M+H]⁺ 356

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.47 (m, 16H), 1.63 (m, 2H), 1.74 (m,2H), 2.35 (t, 2H), 2.57 (t, 2H), 2.84 (s, 4H), 7.85-10.50 (br, 1H).

IR (cm⁻¹): 2920, 2850, 1825, 1790, 1740, 1725, 1710, 1210, 1070

Example 7 Synthesis of N-(15-carboxypentadecanoyloxy)phthalimide

In 15 ml of anhydrous tetrahydrofuran 1,16-hexadecanedioic acid (500 mg,1.75 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxyphthalimide (285 mg, 1.75 mmoles) in 10 ml ofanhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(1.4 mg) and the mixture was stirred for 30 minutes. To the mixture wasadded a solution of DCC (361 mg, 1.75 mmoles) in 3 ml of anhydroustetrahydrofuran and the resulting mixture was stirred overnight. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was separated and purified by silica gelchromatography, to give N-(15-carboxypentadecanoyloxy)phthalimide (310mg, 41%) having the following properties.

m.p. 109°-110.5° C.

FD-MS (m/z): [M+H]⁺ 432

¹ H-NMR (CDCl₃, 270 MHz): δ 1.14-1.50 (m, 20H), 1.63 (m, 2H), 1.78 (m,2H), 2.34 (t, 2H), 2.66 (t, 2H), 7.72-7.94 (m, 4H).

Example 8 Synthesis ofN-(15-carboxypentadecanoyloxy)tetramethylphthalimide

In 3 ml of anhydrous tetrahydrofuran 1,16-hexadecanedioic acid (100 mg,0.35 mmoles) was dissolved. To the obtained solution, were added asolution of N-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles) in 2 mlof anhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride(0.3 mg) and the mixture was stirred for 30 minutes. To the mixture wasadded a solution of DCC (72 mg, 0.35 mmoles) in 0.5 ml of anhydroustetrahydrofuran and the resulting mixture was stirred overnight. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was separated and purified by silica gelchromatography, to giveN-(15-carboxypentadecanoyloxy)-tetramethylphthalimide (58 mg, 34%)having the following properties.

FD-MS (m/z): [M+H]⁺ 488

¹ H-NMR (CDCl₃, 270 MHz): δ 1.14-1.49 (m, 20H), 1.61 (m, 2H) 1.78 (m,2H), 2.29 (s, 6H), 2.34 (t, 2H), 2.66 (t, s, 8H).

Example 9 Synthesis ofN-(15-carboxypentadecanoyloxy)-5-norbornene-2,3-dicarboximide

Example 7 was repeated except for using, instead of N-hydroxyphthalimide(285 mg, 1.75 mmoles), N-hydroxy-5-norbornene-2,3-dicarboximide (313 mg,11.75 mmoles) to obtainN-(15-carboxypentadecanoyloxy)-5-norbornene-2,3-dicarboximide (340 mg,44%) having the following properties.

m.p. 103°-104.5° C.

FD-MS (m/z): [M+H]⁺ 448

¹ H-NMR (CDCl₃, 270 MHz): δ 1.14-1.43 (m, 20H), 1.48-1.82 (m, 6H), 2.34(t, 2H), 2.52 (t, 2H) 3.32 (s, 2H), 3.44 (s, 2H) 6.19 (s, 2H).

Example 10 (a) Synthesis ofN-(15-benzyloxycarbonylpentadecanoyloxy)-tartrimide

In 1.5 ml of tetrahydrofuran N-hydroxytartrimide (59 mg, 0.40 mmole) wasdissolved. To the obtained solution, were added a solution of1,16-hexadecanedioic acid monobenzyl ester (150 mg, 0.40 mmole) and asolution of DCC (83 mg, 0.40 mmole) in 0.5 ml of tetrahydrofuran and theresulting mixture was stirred overnight at 4° C. The reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was separated and purified by silica gel chromatography, togive N-(15-benzyloxycarbonylpentadecanoyloxy)tartrimide (7 mg, 4%)having the following properties.

¹ H-NMR (CDCl₃, 270 MHz): δ 1.14-1.45 (m, 20H), 1.51-1.80 (m, 4H), 2.34(t, 2H), 2.59 (t, 2H), 3.28 (br, 2H), 4.73 (s, 2H), 5.11 (s, 2H), 7.33(s, 5H).

(b) Synthesis of N-(15-carboxypentadecanoyloxy)tartrimide

In 1 ml of tetrahydrofuranN-(15-benzyloxycarbonylpentadecanoyloxy)tartrimide (7 mg, 0.0014 mmole)was dissolved. To the obtained solution, was added 1 mg of 10% palladiumcarbon and the mixture was stirred for 1 hour under an atmosphere ofhydrogen. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure, to giveN-(15-carboxypentadecanoyloxy)tartrimide (5 mg, 87%) having thefollowing properties.

FD-MS (m/z): [M+H]⁺ 416

¹ H-NMR (DMSO-d₆, 270 MHz): δ 1.05-1.40 (m, 20H), 1.48 (m, 2H), 1.62 (m,2H), 2.18 (t, 2H), 2.51 (t, 2H), 4.51 (br, 2H), 6.10-7.50 (br, 1H).

Example 11 (a) Synthesis ofN-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimide sodium salt

In 0.4 ml of anhydrous dimethyl formamide was dissolved1,14-tetradecanedioic acid monobenzyl ester (100 mg, 0.29 mmole). To theobtained solution were added sodium N-hydroxysulfosuccinimide (63 mg,0.29 mmole) and a solution of DCC (65 mg, 0.29 mmole) in 0.4 ml ofanhydrous dimethylformamide and the resulting mixture was stirred for 14hours at a room temperature. The reaction mixture was filtered and thefiltrate was stirred for 2 hours at a temperature under ice cooling. Thesolid that formed was collected by filtration and dried under reducedpressure to give N-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimidesodium salt (66 mg, 42%) having the following properties.

¹ H-NMR (DMSO-d₆, 270 MHz): δ 1.13-1.42 (m, 16H), 1.47-1.68 (m, 4H),2.33 (t, 2H), 2.63 (t, 2H), 2.87 (d, 1H) 3.14 (m, 1H), 3.94 (m, 1H) 5.08(s, 2H), 7.34 (s, 5H).

(b) Synthesis of N-(13-carboxytridecanoyloxy)sulfosuccinimide sodiumsalt

In 1 ml of dimethylformamide was dissolvedN-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimide sodium salt (50mg, 0.11 mmole). To the obtained solution, was added 5 mg of 10%palladium carbon and the mixture was stirred for 20 hours under anatmosphere of hydrogen. The reaction mixture was filtered and to thefiltrate 30 ml of ethyl acetate was added. The mixture was stirred for30 minutes and the solid that formed was collected by filtration anddried under reduced pressure to giveN-(13-carboxytridecanoyloxy)sulfosuccinimide sodium salt (22 mg, 63%)having the following properties.

FAB-MS (m/z): 480, 458, 435, 413

¹ H-NMR (DMSO-d₆, 270 MHz): δ 1.15-1.39 (m, 16H), 1.47 (m, 2H), 1.60 (m,2H), 2.17 (t, 2H), 2.63 (t, 2H), 2.87 (d, 1H), 3.14 (m, 1H), 3.94 (m,1H).

Example 12 Synthesis ofN-(15-carboxypentadecanoyloxy)-3-isopropylsuccinimide

Example 8 was repeated except for using, instead ofN-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles),N-hydroxy-3-isopropylsuccinimide (55 mg, 0.35 mmoles) to obtainN-(15-carboxypentadecanoyloxy)-3-isopropylsuccinimide (42 mg, 28%)having the following properties.

FD-MS (m/z): [M+H]⁺ 426

¹ H-NMR (CDCl₃, 270 MHz): δ 0.80 (d, 3H), 1.00 (d, 3H) 1.18-1.45 (m,20H), 1.62 (m, 2H), 1.74 (m, 2H) 2.34 (m, 3H), 2.55 (dd, 1H) 2.60 (t,2H), 2.79 (dd, 1H) 2.91 (m, 1H).

Example 13 Synthesis ofN-(15-carboxypentadecanoyloxy)tetramethylsuccinimide

Example 8 was repeated except for using, instead ofN-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles),N-hydroxytetramethylsuccinimide (60 mg, 0.35 mmoles) to obtainN-(15-carboxypentadecanoyloxy)tetramethylsuccinimide (40 mg, 26%) havingthe following properties.

FD-MS (m/z): [M+H]⁺ 440

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.46 (m, 32H), 1.62 (m, 2H), 1.74 (m,2H) 2.34 (t, 2H), 2.60 (t, 2H)

Example 14 Synthesis ofN-(15-carboxypentadecanoyloxy)-3-benzylsuccinimide

Example 8 was repeated except for using, instead ofN-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles),N-hydroxy-3-benzylsuccinimide (72 mg, 0.35 mmoles) to obtainN-(15-carboxypentadecanoyloxy)-3-benzylsuccinimide (45 mg, 27%) havingthe following properties.

FD-MS (m/z): [M+H]⁺ 474

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.45 (m, 20H), 1.62 (m, 2H), 1.74 (m,2H) 2.30-2.92 (m, 9H), 7.06 (s, 5H).

Example 15 Synthesis of N-(15-carboxypentadecanoyloxy)itaconimide

Example 8 was repeated except for using, instead ofN-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles),N-hydroxyitaconimide (44 mg, 0.35 mmoles) to obtainN-(15-carboxypentadecanoyloxy)itaconimide (49 mg, 31%) having thefollowing properties.

FD-MS (m/z): [M+H]⁺ 396

¹ H-NMR (CDCl₃, 270 MHz): δ 1.19-1.44 (m, 20H), 1.62 (m, 2H), 1.74 (m,2H) 2.34 (t, 2H), 2.60 (t, 2H) 3.70 (t, 2H) 6.00-6.59 (m, 2H).

Example 16 Synthesis of N-(15-carboxypentadecanoyloxy)glutarimide

Example 8 was repeated except for using, instead ofN-hydroxytetramethylphthalimide (77 mg, 0.35 mmoles),N-hydroxyglutarimide (45 mg, 0.35 mmoles) to obtainN-(15-carboxypentadecanoyloxy)glutarimide (40 mg, 29%) having thefollowing properties.

FD-MS (m/z): [M+H]⁺ 398

¹ H-NMR (CDCl₃, 270 MHz): δ 1.18-1.47 (m, 20H), 1.63 (m, 2H), 1.74 (m,2H) 2.02 (m, 2H), 2.35 (t, 2H) 2.50-2.70 (m 4H), 7.85-10.50 (br, 1H).

Reference Example 1 Synthesis of an SOD derivative by the reaction ofN-(13-carboxytridecanoyloxy)succinimide with SOD

To 1.4 ml of an aqueous solution human erythrocyte-type SOD (71.2 mg/ml)was added 2.6 ml of 0.5M aqueous sodium hydrogencarbonate solution (pH8.0). To the mixture was gradually added with stirring a solution of10.1 mg of the N-(13-carboxytridecanoyloxy)succinimide obtained inExample 6 in 0.2 ml of dimethyl sulfoxide, and the resulting mixture wasstirred overnight at a room temperature. The reaction mixture wasfiltered and the filtrate was subjected to gel filtration using a columnpacked with Sephadex G-25 (trademark; Pharmacia Fine Chemicals) (eluent:10 mM aqueous ammonium hydrogencarbonate solution) and thehigh-molecular-weight fractions were collected. The obtained fractionsas such were subjected to ion-exchange chromatography usingDEAE-Sepharose Fast Flow (trademark; Pharmacia Fine Chemicals) whereelution was successively conducted with an eluent of a mixture of 10 mMTris-hydrochloric acid butter (pH 8) and 0.15M aqueous sodium chloridesolution, that of a mixture of 10 mM Tris-hydrochloric acid butter (pH8) and 0.20M aqueous sodium chloride solution, and finally that of amixture of 10 mM Tris-hydrochloric acid butter (pH 8) and 0.25M aqueoussodium chloride solution, to collect the corresponding fractions(hereinafter these fractions are referred to as fraction-A, fraction-Band fraction-C, respectively). These fractions were each subjected togel filtration by using a column packed with Sephadex G-25 (eluent: 10mM aqueous ammonium hydrogencarbonate solution), desalinized and thehigh-molecular-weight fractions were combined and lyophilized to give 33mg of an SOD derivative (hereinafter referred to as SOD derivative-A),18 mg of an SOD derivative (hereinafter referred to as SODderivative-B), and 15 mg of an SOD derivative (hereinafter referred toas SOD derivative-C, from fraction-A, fraction-B and fraction-C,respectively. Quantitative determination of the amino groups of each ofthe SOD derivatives-A, -B and -C, revealed that 3.6 groups, 4.4 groupsand 5.4 groups of the total amino groups in the starting material SODhad been modified, in the SOD derivatives-A, -B and -C, respectively.

The schematic electrophorograms of the SOD used and the SOD derivative-Cobtained are shown in FIG. 1(a) and (b). FIG. 2 shows an IR spectrum ofthe SOD derivative-C.

Reference Example 2 Synthesis of an SOD derivative by the reaction ofN-(17-carboxyneptadecanoyloxy)succinimide with SOD

To 1.12 ml of an aqueous solution of human erythrocytetype SOD (71.2mg/ml) were added 1.88 ml of water and 0.8 ml of 0.5M aqueous sodiumhydrogencarbonate solution (pH 8.0). To the mixture was gradually addedwith stirring a solution of 3.9 mg of theN-(17-carboxyheptadecanoyloxy)succinimide obtained in Example 3 in 0.2ml of dimethyl sulfoxide, and the resulting mixture was stirredovernight at a room temperature. The reaction mixture was filtered andthe filtrate was subjected to gel filtration using a column packed withSephadex G-25 (trademark; Pharmacia Fine Chemicals) (eluent: 10 mMaqueous ammonium hydrogencarbonate solution) and thehigh-molecular-weight fractions were collected. The obtained fractionsas such were subjected to ion-exchange chromatography usingDEAE-Sepharose Fast Flow (trademark; Pharmacia Fine Chemicals) [eluent:a mixture of 10 mM Tris-hydrochloric acid butter (pH 8) and 0.20Maqueous sodium chloride solution] and the fractions containing theresulting SOD derivative were collected. The obtained fractions weresubjected to gel filtration by using a column packed with Sephadex G-25(eluent: 10 mM aqueous ammonium hydrocarbonate solution), desalinizedand the high-molecular-weight fractions were combined and lyophilized togive 18 mg of the SOD derivative. Quantitative determination by TNBSmethod of the amino groups in the obtained SOD derivative revealed that2.0 pieces of the total amino groups contained in the starting materialSOD had been modified.

The schematic electrophorograms of the SOD used and the SOD derivativeobtained are shown in FIG. 3(a) and (b). FIG. 4 shows an IR spectrum ofthe SOD derivative.

Reference Example 3 Synthesis of an SOD Derivative by the Reaction ofN-(19-carboxynonadecanoyloxy)succinimide with SOD

Reference Example 2 was repeated except for using, instead of 3.9 mg ofN-(17-carboxyheptadecanoyoxy)succinimide, 4.1 mg of theN-(19-carboxynonadecanoyloxy)succinimide obtained in Example 4, toobtain 14 mg of an SOD derivative. Quantitative determination by TNBSmethod of the amino groups in the obtained SOD derivative revealed that2.0 pieces of the total amino groups contained in the starting materialSOD had been modified.

The schematic electrophorograms of the SOD used and the SOD derivativeobtained are shown in FIG. 5(a) and (b). FIG. 6 shows an IR spectrum ofthe SOD derivative.

Reference Example 4 Synthesis of an NCS Derivative by the Reaction ofNCS with N-(15-carboxypentadecanoyloxy)succinimide

In 18 ml of a 0.5M aqueous sodium hydrogencarbonate solution wasdissolved 50 mg of NCS. To the solution obtained, a solution prepared bydissolving 79.8 mg of the N-(15-carboxypentadecanoyloxy)succinimideobtained in Example 2 in 2 ml of dimethyl sulfoxide was gradually addedwith stirring. The mixture was stirred at 4° C. in a light-shieldedplaced for 2 weeks. The reaction mixture was filtered, and the filtratewas subjected to gel filtration using a column packed with Sephadex G-25(eluent: 10 mM aqueous ammonium hydrogencarbonate solution) and thehigh-molecular-weight fractions were collected. The obtained fractionsas such were subjected to ion-exchange chromatography usingDEAE-Sepharose Fast Flow (eluent: a mixture of 10 mM Tris-hydrochloricacid butter (pH 8) and 0.20M aqueous sodium chloride solution), and thefractions containing the resulting NCS derivative were collected. Theobtained fractions were subjected to gel filtration by using a columnpacked with Sephadex G-25 (eluent: 10 mM aqueous ammoniumhydrogencarbonate solution), desalinized and the high-molecular-weightfractions were combined and lyophilized to give 7 mg of the NCSderivative. From the obtained NCS derivative no free amino group wasdetected by quantitative determination by TNBS method.

The schematic electrophorograms of the NCS used and the NCS derivativeobtained are shown in FIG. 7(a) and (b). FIG. 8 shows an IR spectrum ofthe NCS derivative.

Reference Example 5 Synthesis of an NCS Derivative by the Reaction ofN-(17-carboxyheptadecanoyloxy)succinimide with NCS

Reference Example 4 was repeated except for using, instead of 79.8 mg ofN-(15-carboxypentadecanoyloxy)succinimide, 85.6 mg of theN-(17-carboxyheptadecanoyloxy)succinimide obtained in Example 3, toobtain 5 mg of an NCS derivative. Quantitative determination by TNBSmethod of the amino groups in the obtained NCS derivative revealed thatit contained no free amino groups.

The schematic electrophorograms of the NCS used and the NCS derivativeobtained are shown in FIG. 9 (a) and (b). FIG. 10 shows an IR spectrumof the NCS derivative.

Test Example 1 Plasma Clearance of SOD Derivatives

Under pentobarbital anesthsia, rats (Wistar strain, male, 7 weeks ofage, body weight about 200 g) were cannulated into the femoral vein andwere heparinized intravenously (1000 U/ml, 0.2 ml/rat). Then, a specimensolution of SOD or SOD derivative in saline (10 mg/ml) was injected intothe femoral vein of each rat in an amount of 0.2 ml/rat. At timedintervals, 0.2 ml blood samples were collected from the femoral vein andthe time courses of plasma SOD concentrations were determined bymeasuring the SOD activities in plasma. The time courses of the plasmaconcentrations of the SOD and the SOD derivatives are shown in FIG. 11.

Test Example 2 Effect of SOD derivative on acute gastric mucosal lesion(gastric ulcer)

Male SD rats (body weight: about 200 g) were fasted overnight and wereplaced in restraint cages in groups of each 3 rats. The cages werevertically immersed upto the level of xyphoid process in water at 22° C.After 6 hours of stress loading, the cages were taken out from the waterand the rats were exsanguinated. Their stomachs were fixed by 1%formalin. After this fixation, the lengths of linear ulcers were totaledand the sum was expressed as the ulcer index.

Rats in the control group received 0.5 ml each of saline, while rats inthe test group received 0.2 ml each of a solution of the SOD derivativeobtained in Reference Example 1 and weighing 2 mg/rat, all byintravenous route 5 minutes before restraint water-immersion.

The obtained results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Ulcer index                                                                   ______________________________________                                        Control        31.3 ± 8.1 (30.1, 23.9, 39.9)                               Test           14.8 ± 6.7 (16.3, 7.5, 20.6)                                ______________________________________                                    

As is apparent from Table 1, the SOD derivative exhibited an excellentanti-ulcer activity in the test group.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the bore teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. A compound of the formula ##STR11## or a saltthereof, wherein W is a divalent long chain hydrocarbon radical havingfrom 8 to 28 principal chain atoms; and wherein R², R³, R⁴ and R⁵, incombination with the carbon atoms to which they bond, form a benzene,cyclohexane, cyclopentane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hepta-2-ene, 7-oxabicyclo[2.2.1]heptane or7-oxabicyclo[2.2.1]hepta-2-ene ring system which is optionallysubstituted by --SO₃ H, --CO₂ H, --OH, F, Cl, Br, I, --CH₃ or --OCH₃. 2.The compound according to claim 1, wherein the divalent hydrocarbonradical W has from 10 to 20 principal chain atoms.
 3. The compoundaccording to claim 2, wherein W is a divalent radical of the formula(CH₂)₁₀, (CH₂)₁₁, (CH₂)₁₂, (CH₂)₁₃, (CH₂)₁₄, (CH₂)₁₅, (CH₂)₁₆, (CH₂)₁₇,(CH₂)₁₈, (CH₂)₁₉, (CH₂)₂₀, CH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CH(CH₂)₇, (CH₂)₃CH═CH(CH₂)₇, (CH₂)₄ CH═CH(CH₂)₇, (CH₂)₅ CH═CH(CH₂)₇, (CH₂)₆ CH═CH(CH₂)₇,(CH₂)₇ CH═CH(CH₂)₇, (CH₂)₈ CH═CH(CH₂)₇, (CH₂)₉ CH═CH(CH₂)₇, (CH₂)₁₀CH═CH(CH₂)₇, (CH₂)₁₁ CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂, (CH₂)₈ CH═CH(CH₂)₂,(CH₂)₈ CH═CH(CH₂)₃, (CH₂)₈ CH═CH(CH₂)₄, (CH₂)₈ CH═CH(CH₂)₅, (CH₂)₈CH═CH(CH₂)₆, (CH₂)₈ CH═CH(CH₂)₈, (CH₂)₈ CH═CH(CH₂)₉, (CH₂)₈CH═CH(CH₂)₁₀, CH₂ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CHCH₂ CH═CH(CH₂)₇,(CH₂)₃ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₄ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₅CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₆ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₇ CH═CHCH₂CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂ CH═CH(CH₂)₇.
 4. The compound according toclaim 1, wherein ##STR12## is a radical of the formula ##STR13##
 5. Thecompound according to claim 1, which is an alkali metal or alkalineearth metal salt.
 6. The compound according to claim 1, which isN-(15-carboxypentadecanoyloxy)phthalimide.
 7. The compound according toclaim 1, which is N-(15-carboxypentadecanoyloxy)tetramethylphthalimide.8. The compound according to claim 1, which isN-(15-carboxypentadecanoyloxy)-5-norbornene-2,3-dicarboximide.
 9. Acompound of the formula or a salt thereof, wherein W is a divalent longchain hydrocarbon radical having from 8 to 28 principal chain atoms; andwherein each of R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, which can be the sameor different, is a hydrogen atom; an alkyl radical; an aryl radical; anaralkyl radical; an --SO₃ H group; a radical of the formula --OH⁶wherein R⁶ is selected from the group consisting of a hydrogen atom, analkyl radical, an aryl radical, an aralkyl radical and an acyl radical;a radical of the formula --NR⁷ R⁸ wherein each of R⁷ and R⁸, which canbe the same or different, is selected from the group consisting of analkyl radical, an aryl radical, an aralkyl radical and an acyl radical;or a radical of the formula --CO₂ R⁹ wherein R⁹ is selected from thegroup consisting of a hydrogen atom, an alkyl radical, an aryl radicalor an aralkyl radical.
 10. The compound according to claim 9, whereinthe divalent hydrocarbon radical W has from 10 to 20 principal chainatoms.
 11. The compound according to claim 10, wherein W is a divalentradical of the formula (CH₂)₁₀, (CH₂)₁₁, .[.(CH₂)₁₂ (CH₂)₁₃ (CH₂)₁₄,.]..Iadd.(CH₂)₁₂, (CH₂)₁₃, (CH₂)₁₄, .Iaddend.(CH₂)₁₅, (CH₂)₁₆, (CH₂)₁₇,(CH₂)₁₈, (CH₂)₁₉, (CH₂)₂₀, CH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CH(CH₂)₇, (CH₂)₃CH═CH(CH₂)₇, (CH₂)₄ CH═CH(CH₂)₇, (CH₂)₅ CH═CH(CH₂)₇, (CH₂)₆ CH═CH(CH₂)₇,(CH₂)₇ CH═CH(CH₂)₇, (CH₂)₈ CH═CH(CH₂)₇, (CH₂)₉ CH═CH(CH₂)₇, (CH₂)₁₀CH═CH(CH₂)₇, (CH₂)₁₁ CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂, (CH₂)₈ CH═CH(CH₂)₂,(CH₂)₈ CH═CH(CH₂)₃, (CH₂)₈ CH═CH(CH₂)₄, (CH₂)₈ CH═CH(CH₂)₅, (CH₂)₈CH═CH(CH₂)₆, (CH₂)₈ CH═CH(CH₂)₈, (CH₂)₈ CH═CH(CH₂)₉, (CH₂)₈CH═CH(CH₂)₁₀, CH₂ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CHCH₂ CH═CH(CH₂)₇,.[.(CH₂)₃ CH═CHCH₂ CH═(CH₂)₇,.]. .Iadd.(CH₂)₃ CH═CHCH₂ CH═CH(CH₂)₇,.Iaddend.(CH₂)₄ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₅ CH═CHCH₂ CH═CH(CH₂)₇,(CH₂)₆ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₇ CH═CHCH₂ CH═CH(CH₂)₇, or (CH₂)₈CH═CHCH₂ CH═CH(CH₂)₇.
 12. The compound according to claim 9, whereineach of R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, which can be the same ordifferent, is hydrogen, methyl, ethyl, propyl, isopropyl, octadecyl,phenyl, p-bromophenyl, benzyl, p-methoxybenzyl, --SO₃ H, hydroxy,methoxy, ethoxy, propoxy, isopropoxy, phenoxy, p-bromophenoxy,benzyloxy, p-methoxybenzyloxy, acetoxy or benzoyloxy; or a radical ofthe formula --NR⁷ R⁸ selected from the group consisting ofdimethylamino, diethylamino, N-methylacetamido and N-methylbenzamido; ora radical of the formula --CO₂ R⁹ selected from the group consisting ofcarboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, phenoxycarbonyl and p-bromophenoxycarbonyl.
 13. Thecompound according to claim 9, which is an alkali metal or alkalineearth metal salt.
 14. The compound according to claim 9, which isN-(15-carboxypentadecanoyloxy)glutarimide.
 15. A compound of the formula##STR14## or a salt thereof, wherein W is a divalent long chainhydrocarbon radical interrupted by one or more groups each independentlyselected from the group consisting of an oxygen atom, a sulfur atom andan --N(R¹)-- group wherein R¹ is lower alkyl, said radical W having from8 to 28 principal chain atoms; and ##STR15## is a radical of the formula##STR16## wherein each of R², R³, R⁴ and R⁵, which can be the same ordifferent, is a hydrogen atom; an alkyl radical; an aryl radical; anaralkyl radical; an --SO₃ H group; a radical of the formula --OR⁶wherein R⁶ is selected from the group consisting of a hydrogen atom, analkyl radical, an aryl radical, an aralkyl radical and an acyl radical;a radical of the formula --NR⁷ R⁸ wherein each of R⁷ and R⁸, which canbe the same or different, is selected from the group consisting of analkyl radical, an aryl radical, an aralkyl radical and acyl radical; ora radical of the formula --CO₂ R⁹ wherein R⁹ is selected from the groupconsisting of a hydrogen atom, an alkyl radical, an aryl radical and anaralkyl radical; or R², R³, R⁴ and R⁵ can, in combination with thecarbon atoms to which they bond, form a benzene, cyclohexane,cyclopentane, bicyclo [2.2.1]heptane, bicyclo[2.2.1]hepta-2-ene,7-oxabicyclo[2.2.1]heptane or 7-oxabicyclo[2.2.1]hepta-2-ene ring systemwhich is optionally substituted by --SO₃ H, --CO₂ H, --OH, F, Cl, Br, I,--CH₃ or --OCH₃ ; or R² and R³ and/or R⁴ and R⁵, in combination, can bea methylene or isopropylidene group; and each of R¹⁰, R¹¹, R¹², R¹³, R¹⁴and R¹⁵, which can be the same or different, is a hydrogen atom; analkyl radical; an aryl radical; an aralkyl radical; an --SO₃ H group; aradical of the formula --OR⁶ wherein R⁶ is selected from the groupconsisting of a hydrogen atom, an alkyl radical, an aryl radical, anaralkyl radical and an acyl radical; a radical of the formula --NR⁷ R⁸wherein each of R⁷ and R⁸, which can be the same or different, isselected from the group consisting of an alkyl radical, an aryl radical,an aralkyl radical and an acyl radical; or a radical of the formula--CO₂ R⁹ wherein R⁹ is selected from the group consisting of a hydrogenatom, an alkyl radical, an aryl radical or an aralkyl radical.
 16. Thecompound according to claim 15, wherein the divalent hydrocarbon radicalW has from 10 to 20 principal chain atoms.
 17. The compound according toclaim 15, wherein R¹ is methyl, ethyl, propyl or isopropyl.
 18. Thecompound according to claim 16, wherein W is a divalent radical of theformula (CH₂)₂ --O--(CH₂)₇, (CH₂)₂ --O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₉,(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₂ --O--(CH₂)₁₁, (CH₂)₂ --O--(CH₂)₁₂, (CH₂)₂--O--(CH₂)₁₃, (CH₂)₂ --O--(CH₂)₁₄, (CH₂)₂ --O--(CH₂)₁₅, (CH₂)₂--O--(CH₂)₁₆, (CH₂)₂ --O--(CH₂)₁₇, (CH₂)₄ --O--(CH₂)₅, (CH₂)₄--O--(CH₂)₆, (CH₂)₄ --O--(CH₂)₇, .[.(CH₂)₄ --O--,(CH₂)₈ (CH₂)₄--O--(CH₂)₉,.]. .Iadd.(CH₂)₃ --O--(CH₂)₈, (CH₂)₄ --O--(CH₂)₉,.Iaddend.(CH₂)₄ --O--(CH₂)₁₀, (CH₂)₄ --O--(CH₂)₁₁, (CH₂)₄ --O--(CH₂)₁₂,(CH₂)₄ --O--(CH₂)₁₃, (CH₂)₄ --O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₁₅, (CH₂)₆--O--(CH₂)₃, (CH₂)₆ --O--(CH₂)₄, (CH₂)₆ --O--(CH₂)₅, (CH₂)₆ --O--(CH₂)₆,(CH₂)₆ --O--(CH₂)₇, (CH₂)₆ --O--(CH₂)₈, (CH₂)₆ --O--(CH₂)₉, (CH₂)₆--O--(CH₂)₁₀, (CH₂)₆ --O--(CH₂)₁₁, (CH₂)₆ --O--(CH₂)₁₂, (CH₂)₆--O--(CH₂)₁₃, (CH₂)₈ --O--CH₂, (CH₂)₈ --O--(CH₂)₂, (CH₂)₈ --O--(CH₂)₃,(CH₂)₈ --O--(CH₂)₄, (CH₂)₈ --O--(CH₂)₅, (CH₂)₈ --O--(CH₂)₆, (CH₂)₈--O--(CH₂)₇, (CH₂)₈ --O--(CH₂)₈, (CH₂)₈ --O--(CH₂)₉, (CH₂)₈--O--(CH₂)₁₀, (CH₂)₈ --O--(CH₂)₁₁, (CH₂)₁₀ --O--CH₂, (CH₂)₁₀--O--(CH₂)₂, (CH₂)₁₀ --O--(CH₂)₃, (CH₂)₁₀ --O--(CH₂)₄, (CH₂)₁₀--O--(CH₂)₅, (CH₂)₁₀ --O--(CH₂)₆, (CH₂)₁₀ --O--(CH₂)₇, (CH₂)₁₀--O--(CH₂)₈, (CH₂)₁₀ --O--(CH₂)₉, (CH₂)₁₂ --O--CH₂, (CH₂)₁₂ --O--(CH₂)₂,(CH₂)₁₂ --O--(CH₂)₃, (CH₂)₁₂ --O--(CH₂)₄, (CH₂)₁₂ --O--(CH₂)₅, (CH₂)₁₂--O--(CH₂)₆, (CH₂)₁₂ --O--(CH₂)₇, CH₂ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₂--O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₃ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₄--O--(CH₂)₅ CH═CH(CH₂)₇, or (CH₂)₅ --O--(CH₂)₅ CH═CH(CH₂)₇.
 19. Thecompound according to claim 16, wherein W is a divalent radical of theformula (CH₂)₂ --S--(CH₂)₇, (CH₂)₂ --S--(CH₂)₈, (CH₂)₂ --S--(CH₂)₉,(CH₂)₂ --S--(CH₂)₁₀, (CH₂)₂ --S--(CH₂)₁₁, (CH₂)₂ --S--(CH₂)₁₂, (CH₂)₂--S--(CH₂)₁₃, (CH₂)₂ --S--(CH₂)₁₄, (CH₂)₂ --S--(CH₂)₁₅, (CH₂)₂--S--(CH₂)₁₆, (CH₂)₂ --S--(CH₂)₁₇, (CH₂)₄ --S--(CH₂)₅, (CH₂)₄--S--(CH₂)₆, (CH₂)₄ --S--(CH₂)₇, (CH₂)₄ --S--(CH₂)₈, (CH₂)₄ --S--(CH₂)₉,(CH₂)₄ --S--(CH₂)₁₀, (CH₂)₄ --S--(CH₂)₁₁, (CH₂)₄ --S--(CH₂)₁₂, (CH₂)₄--S--(CH₂)₁₃, (CH₂)₄ --S--(CH₂)₁₄, (CH₂)₄ --S--(CH₂)₁₅, (CH₂)₆--S--(CH₂)₃, (CH₂)₆ --S--(CH₂)₄, (CH₂)₆ --S--(CH₂)₅, (CH₂)₆ --S--(CH₂)₆,(CH₂)₆ --S--(CH₂)₇, (CH₂)₆ --S--(CH₂)₈, (CH₂)₆ --S--(CH₂)₉, (CH₂)₆--S--(CH₂)₁₀, (CH₂)₆ --S--(CH₂)₁₁, (CH₂)₆ --S--(CH₂)₁₂, (CH₂)₆--S--(CH₂)₁₃, (CH₂)₈ --S--CH₂, (CH₂)₈ --S--(CH₂)₂, (CH₂)₈ --S--(CH₂)₃,(CH₂)₈ --S--(CH₂)₄, (CH₂)₈ --S--(CH₂)₅, (CH₂)₈ --S--(CH₂)₆, (CH₂)₈--S--(CH₂)₇, (CH₂)₈ --S--(CH₂)₈, (CH₂)₈ --S--(CH₂)₉, (CH₂)₈--S--(CH₂)₁₀, (CH₂)₈ --S--(CH₂)₁₁, (CH₂)₁₀ --S--CH₂, (CH₂)₁₀--S--(CH₂)₂, (CH₂)₁₀ --S--(CH₂)₃, (CH₂)₁₀ --S--(CH₂)₄, (CH₂)₁₀--S--(CH₂)₅, (CH₂)₁₀ --S--(CH₂)₆, (CH₂)₁₀ --S--(CH₂)₇, (CH₂)₁₀--S--(CH₂)₈, .[.(CH₂)₁₀ --S--(CH₂)₉),.]. .Iadd.(CH₂)₁₀ --S--(CH₂)₉,.Iaddend.(CH₂)₁₂ --S--CH₂, (CH₂)₁₂ --S--(CH₂)₂, (CH₂)₁₂ --S--(CH₂)₃,(CH₂)₁₂ --S--(CH₂)₄, (CH₂)₁₂ --S--(CH₂)₅, (CH₂)₁₂ --S--(CH₂)₆, or(CH₂)₁₂ --S--(CH₂)₇.
 20. The compound according to claim 16, wherein Wis a divalent radical of the formula (CH₂)₂ --N(CH₃)--(CH₂)₇, (CH₂)₂--N(CH₃)--(CH₂)₈, (CH₂)₂ --N(CH₃)--(CH₂)₉, (CH₂)₂ --N(CH₃)--(CH₂)₁₀,(CH₂)₂ --N(CH₃)--(CH₂)₁₁, (CH₂)₂ --N(CH₃)--(CH₂)₁₂, (CH₂)₂--N(CH₃)--(CH₂)₁₃, (CH₂)₂ --N(CH₃)--(CH₂)₁₄, (CH₂)₂ --N(CH₃)--(CH₂)₁₅,(CH₂)₂ --N(CH₃)--(CH₂)₁₆, (CH₂)₂ --N(CH₃)--(CH₂)₁₇, (CH₂)₄--N(CH₃)--(CH₂)₅, (CH₂)₄ --N(CH₃)--(CH₂)₆, (CH₂)₄ --N(CH₃)--(CH₂)₇,(CH₂)₄ --N(CH₃)--(CH₂)₈, (CH₂)₄ --N(CH₃)--(CH₂)₉, (CH₂)₄--N(CH₃)--(CH₂)₁₀, (CH₂)₄ --N(CH₃)--(CH₂)₁₁, (CH₂)₄ --N(CH₃)--(CH₂)₁₂,(CH₂)₄ --N(CH₃)--(CH₂)₁₃, (CH₂)₄ --N(CH₃)--(CH₂)₁₄, (CH₂)₄--N(CH₃)--(CH₂)₁₅, (CH₂)₆ --N(CH₃)--(CH₂)₃, (CH₂)₆ --N(CH₃)--(CH₂)₄,(CH₂)₆ --N(CH₃)--(CH₂)₅, (CH₂)₆ --N(CH₃)--(CH₂)₆, (CH₂)₆--N(CH₃)--(CH₂)₇, (CH₂)₆ --N(CH₃)--(CH₂)₈, (CH₂)₆ --N(CH₃)--(CH₂)₉,(CH₂)₆ --N(CH₃)--(CH₂)₁₀, (CH₂)₆ --N(CH₃)--(CH₂)₁₁, (CH₂)₆--N(CH₃)--(CH₂)₁₂, (CH₂)₆ --N(CH₃)--(CH₂)₁₃, (CH₂)₂ --N(C₂ H₅)--(CH₂)₇,(CH₂)₂ --N(C₂ H₅)--(CH₂)₈, (CH₂)₂ --N(C₂ H₅)--(CH₂)₉, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₀, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₂,(CH₂)₂ --N(C₂ H₅)--(CH₂)₁₃, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₄, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₅, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₆, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₇,(CH₂)₄ --N(C₂ H₅)--(CH₂)₅, (CH₂)₄ --N(C₂ H₅)--(CH₂)₆, (CH₂)₄ --N(C₂H₅)--(CH₂)₇, (CH₂)₄ --N(C₂ H₅)--(CH₂)₈, (CH₂)₄ --N(C₂ H₅)--(CH₂)₉,(CH₂)₄ --N(C₂ H₅)--(CH₂)₁₀, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₄ --N(C₂H₅)--(CH₂)₁₂, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₃, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₄,(CH₂)₄ --N(C₂ H₅)--(CH₂)₁₅, (CH₂)₆ --N(C₂ H₅)--(CH₂)₃, (CH₂)₆ --N(C₂H₅)--(CH₂)₄, (CH₂)₆ --N(C₂ H₅)--(CH₂)₅, (CH₂)₆ --N(C₂ H₅)--(CH₂)₆,(CH₂)₆ --N(C₂ H₅)--(CH₂)₇, (CH₂)₆ --N(C₂ H₅)--(CH₂)₈, (CH₂)₆ --N(C₂H₅)--(CH₂)₉, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₀, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₁,(CH₂)₆ --N(C₂ H₅)--(CH₂)₁₂, or (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₃.
 21. Thecompound according to claim 16, wherein W is a divalent radical of theformula (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₅,(CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₇, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₉, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₁, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₂, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₃, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₂, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₃, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₅, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₇, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₉, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₁₁, or (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₂.
 22. Thecompound according to claim 16, wherein W is a divalent radical of theformula (CH₂)₂ --S--S--(CH₂)₇, (CH₂)₂ --S--S--(CH₂)₉, (CH₂)₂--S--S--(CH₂)₁₁, (CH₂)₂ --S--S--(CH₂)₁₃, (CH₂)₂ --S--S--(CH₂)₁₅, (CH₂)₄--S--S--(CH₂)₅, (CH₂)₄ --S--S--(CH₂)₇, (CH₂)₄ --S--S--(CH₂)₉, (CH₂)₄--S--S--(CH₂)₁₁, (CH₂)₄ --S--S--(CH₂)₁₃, (CH₂)₆ --S--S--(CH₂)₃, (CH₂)₆--S--S--(CH₂)₅, (CH₂)₆ --S--S--(CH₂)₇, (CH₂)₆ --S--S--(CH₂)₉, (CH₂)₆--S--S--(CH₂)₁₁, (CH₂)₈ --S--S--CH₂, (CH₂)₈ --S--S--(CH₂)₃, (CH₂)₈--S--S--(CH₂)₅, (CH₂)₈ --S--S--(CH₂)₇, or (CH₂)₈ --S--S--(CH₂)₉.
 23. Thecompound according to claim 15, wherein ##STR17## is a radical of theformula ##STR18## wherein each of R², R³, R⁴ and R⁵, which can be thesame or different, is a hydrogen atom; an alkyl radical; an arylradical; an aralkyl radical; an --SO₃ H group; a radical of the formula--OR⁶ wherein R⁶ is selected from the group consisting of a hydrogenatom, an alkyl radical, an aryl radical, an aralkyl radical and an acylradical; a radical of the formula --NR⁷ R⁸ wherein each of R⁷ and R⁸,which can be the same or different, is selected from the groupconsisting of an alkyl radical, an aryl radical, an aralkyl radical andacyl radical; or a radical of the formula --CO₂ R⁹ wherein R⁹ isselected from the group consisting of a hydrogen atom, an alkyl radical,an aryl radical and an aralkyl radical; or R², R³, R⁴ and R⁵ can, incombination with the carbon atoms to which they bond, form a benzene,cyclohexane, cyclopentane, bicyclo [2.2.1]heptane,bicyclo[2.2.1]hepta-2-ene, 7-oxabicyclo[2.2.1]heptane or7-oxabicyclo[2.2.1]hepta-2-ene ring system which is optionallysubstituted by --SO₃ H, --CO₂ H, --OH, F, Cl, Br, I, --CH₃ or --OCH₃ ;or R² and R³ and/or R⁴ and R⁵, in combination, can be a methylene orisopropylidene group.
 24. The compound according to claim 23, whereinR², R³, R⁴ and R⁵, in combination with the carbon atoms to which theybond, form a benzene, cyclohexane, cyclopentane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hepta-2-ene, 7-oxabicyclo[2.2.1]heptane or7-oxabicyclo[2.2.1]hepta-2-ene ring system which is optionallysubstituted by --SO₃ H, --CO₂ H, --OH, F, Cl, Br, I, --CH₃ or --OCH₃.25. The compound according to claim 23, wherein each of R², R³, R⁴ andR⁵, which can be the same or different, is hydrogen, methyl, ethyl,propyl, isopropyl, octadecyl, phenyl, p-bromophenyl, benzyl,p-methoxybenzyl, --SO₃ H, hydroxy, methoxy, ethoxy, propoxy, isopropoxy,phenoxy, p-bromophenoxy, benzyloxy, p-methoxybenzyloxy, acetoxy orbenzoyloxy; or a radical of the formula --NR⁷ R⁸ selected from the groupconsisting of dimethylamino, diethylamino, N-methylacetamido andN-methylbenzamido; or a radical of the formula --CO₂ R⁹ selected fromthe group consisting of carboxyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl andp-bromophenoxycarbonyl.
 26. The compound according to claim 23, whereinR² and R³ and/or R⁴ and R⁵, in combination, form a methylene orisopropylidene group.
 27. The compound according to claim 26, wherein##STR19## is a radical of the formula ##STR20##
 28. The compoundaccording to claim 24, wherein is a radical of the formula ##STR21## 29.The compound according to claim 15, wherein is a radical of the formula##STR22## wherein each of R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, which can bethe same or different, is a hydrogen atom; an alkyl radical; an arylradical; an aralkyl radical; an --SO₃ H group; a radical of the formula--OR⁶ wherein R⁶ is selected from the group consisting of a hydrogenatom, an alkyl radical, an aryl radical, an aralkyl radical and an acylradical; a radical of the formula --NR⁷ R⁸ wherein each of R⁷ and R⁸,which can be the same or different, is selected from the groupconsisting of an alkyl radical, an aryl radical, an aralkyl radical andan acyl radical; or a radical of the formula --CO₂ R⁹ wherein R⁹ isselected from the group consisting of a hydrogen atom, an alkyl radical,an aryl radical or an aralkyl radical.
 30. The compound according toclaim 29, wherein each of R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, which can bethe same or different, is hydrogen, methyl, ethyl, propyl, isopropyl,octadecyl, phenyl, p-bromophenyl, benzyl, p-methoxybenzyl, --SO₃ H,hydroxy, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, p-bromophenoxy,benzyloxy, p-methoxybenzyloxy, acetoxy or benzoyloxy; or a radical ofthe formula --NR⁷ R⁸ selected from the group consisting ofdimethylamino, diethylamino, N-methylacetamido and N-methylbenzamido; ora radical of the formula --CO₂ R⁹ selected from the group consisting ofcarboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, phenoxycarbonyl and p-bromophenoxycarbonyl.
 31. Thecompound according to claim 15, which is an alkali metal or alkalineearth metal salt. .Iadd.
 32. A protein compound having the formula

    (protein)(Z).sub.n

wherein (protein) represents a pharmacologically active protein having namino radicals each derivable from an amino group by removal of one ofits hydrogen atoms, and (Z) is a radical of a long chain carboxylic acidhaving the formula ##STR23## wherein W is a divalent long chainhydrocarbon radical which is uninterrupted or interrupted by one or moregroups each independently selected from the group consisting of anoxygen atom, a sulfur atom and an --N(R¹) group wherein R¹ is loweralkyl, said radical W having from 8 to 28 principal chain atoms, each(Z) being derivable from a long chain dicarboxylic acid HO₂ C--W--CO₂ Hby removal of a hydroxyl group from one of its carbonyl groups, each (Z)being bonded to one of said n amino radicals in the protein, n being anaverage of the number of amide bonds between (Z) and (protein) and beinga number from 1 to
 8. .Iaddend..Iadd.33. A protein compound according toclaim 32, wherein the divalent radical W has from 10 to 20 principalchain atoms. .Iaddend..Iadd.4. A protein compound according to claim 32,wherein R¹ is methyl, ethyl, propyl or isopropyl. .Iaddend..Iadd.35. Aprotein compound according to claim 33, wherein W is a divalent radicalof the formula (CH₂)₁₀, (CH₂)₁₁, (CH₂)₁₃, (CH₂)₁₄, (CH₂)₁₅, (CH₂)₁₆,(CH₂)₁₇, (CH₂)₁₈, (CH₂)₁₉, (CH₂)₂₀, CH₂ CH--CH(CH₂)₇, (CH₂)₂CH═CH(CH₂)₇, (CH₂)₃ CH═CH(CH₂)₇, (CH₂)₄ CH═CH(CH₂)₇, (CH₂)₅ CH═CH(CH₂)₇,(CH₂)₆ CH═CH(CH₂)₇, (CH₂)₇ CH═CH(CH₂)₇, (CH₂)₈ CH═CH(CH₂)₇, (CH₂)₉CH═CH(CH₂)₇, (CH₂)₁₀ CH═CH(CH₂)₇, (CH₂)₁₁ CH═CH(CH₂)₇, (CH₂)₈ CH═CHCH₂,(CH₂)₈ CH═CH(CH₂)₂, (CH₂)₈ CH═CH(CH₂)₃, (CH₂)₈ CH═CH(CH₂)₄, (CH₂)₈CH═CH(CH₂)₅, (CH₂)₈ CH═CH(CH₂)₆, (CH₂)₈ CH═CH(CH₂)₈, (CH₂)₈ CH═CH(CH₂)₉,(CH₂)₈ CH═CH(CH₂)₁₀, CH₂ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₂ CH═CHCH₂CH═CH(CH₂)₇, (CH₂)₃ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₄ CH═CHCH₂ CH═CH(CH₂)₇,(CH₂)₅ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₆ CH═CHCH₂ CH═CH(CH₂)₇, (CH₂)₇CH═CHCH₂ CH═CH(CH₂)₇, or (CH₂)₈ CH═CHCH₂ CH═CH(CH₂)₇. .Iaddend..Iadd.36.A protein compound according to claim 35, wherein W is a divalent groupof the formula (CH₂)₁₂, (CH₂)₁₄, (CH₂)₁₆, (CH₂)₁₈ or (CH₂)₂₀..Iaddend..Iadd.37. A protein compound according to claim 33, wherein Wis a divalent radical of the formula (CH₂)₂ --O--(CH₂)₇, (CH₂)₂--O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₉, (CH₂)₂ --O--(CH₂)₁₀, (CH₂)₂--O--(CH₂)₁₁, (CH₂)₂ --O--(CH₂)₁₂, (CH₂)₂ --O--(CH₂)₁₃, (CH₂)₂--O--(CH₂)₁₄, (CH₂)₂ --O--(CH₂)₁₅, (CH₂)₂ --O--(CH₂)₁₆, (CH₂)₂--O--(CH₂)₁₇, (CH₂)₄ --O--(CH₂)₅, (CH₂)₄ --O--(CH₂)₆, (CH₂)₄--O--(CH₂)₇, (CH₂)₄ --O--(CH₂)₈, (CH₂)₄ --O--(CH₂)₉, (CH₂)₄--O--(CH₂)₁₀, (CH₂)₄ --O--(CH₂)₁₁, (CH₂)₄ --O--(CH₂)₁₂, (CH₂)₄--O--(CH₂)₁₃, (CH₂)₄ --O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₁₅, (CH₂)₆--O--(CH₂)₃, (CH₂)₆ --O--(CH₂)₄, (CH₂)₆ --O--(CH₂)₅, (CH₂)₆ --O--(CH₂)₆,(CH₂)₆ --O--(CH₂)₇, (CH₂)₆ --O--(CH₂)₈, (CH₂)₆ --O--(CH₂)₉, (CH₂)₆--O--(CH₂)₁₀, (CH₂)₆ --O--(CH₂)₁₁, (CH₂)₆ --O--(CH₂)₁₂, (CH₂)₆--O--(CH₂)₁₃, (CH₂)₈ --O--CH₂, (CH₂)₈ --O--(CH₂)₂, (CH₂)₈ --O--(CH₂)₃,(CH₂)₈ --O--(CH₂)₄, (CH₂)₈ --O--(CH₂)₅, (CH₂)₈ --O--(CH₂)₆, (CH₂)₈--O--(CH₂)₇, (CH₂)₈ --O--(CH₂)₈, (CH₂)₈ --O--(CH₂)₉, (CH₂)₈--O--(CH₂)₁₀, (CH₂)₈ --O--(CH₂)₁₁, (CH₂)₁₀ --O--CH₂, (CH₂)₁₀--O--(CH₂)₂, (CH₂)₁₀ --O--(CH₂)₃, (CH₂)₁₀ --O--(CH₂)₄, (CH₂)₁₀--O--(CH₂)₅, (CH₂)₁₀ --O--(CH₂)₆, (CH₂)₁₀ --O--(CH₂)₇, (CH₂)₁₀--O--(CH₂)₈, (CH₂)₁₀ --O--(CH₂)₉, (CH₂)₁₂ --O--CH₂, (CH₂)₁₂ --O--(CH₂)₂,(CH₂)₁₂ --O--(CH₂)₃, (CH₂)₁₂ --O--(CH₂)₄, (CH₂)₁₂ --O--(CH₂)₅, (CH₂)₁₂--O--(CH₂)₆, (CH₂)₁₂ --O--(CH₂)₇, CH₂ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₂--O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₃ --O--(CH₂)₅ CH═CH(CH₂)₇, (CH₂)₄--O--(CH₂)₅ CH═CH(CH₂)₇, or (CH₂)₅ --O--(CH₂)₅ CH═CH(CH₂)₇..Iaddend..Iadd.38. A protein compound according to claim 33, wherein Wis a divalent radical of the formula (CH₂)₂ --S--(CH₂)₇, (CH₂)₂--S--(CH₂)₈, (CH₂)₂ --S--(CH₂)₉, (CH₂)₂ --S--(CH₂)₁₀, (CH₂)₂--S--(CH₂)₁₁, (CH₂)₂ --S--(CH₂)₁₂, (CH₂)₂ --S--(CH₂)₁₃, (CH₂)₂--S--(CH₂)₁₄, (CH₂)₂ --S--(CH₂)₁₅, (CH₂)₂ --S--(CH₂)₁₆, (CH₂)₂--S--(CH₂)₁₇, (CH₂)₄ --S--(CH₂)₅, (CH₂)₄ --S--(CH₂)₆, (CH₂)₄--S--(CH₂)₇, (CH₂)₄ --S--(CH₂)₈, (CH₂)₄ --S--(CH₂)₉, (CH₂)₄--S--(CH₂)₁₀, (CH₂)₄ --S--(CH₂)₁₁, (CH₂)₄ --S--(CH₂)₁₂, (CH₂)₄--S--(CH₂)₁₃, (CH₂)₄ --S--(CH₂)₁₄, (CH₂)₄ --S--(CH₂)₁₅, (CH₂)₆--S--(CH₂)₃, (CH₂)₆ --S--(CH₂)₄, (CH₂)₆ --S--(CH₂)₅, (CH₂)₆ --S--(CH₂)₆,(CH₂)₆ --S--(CH₂)₇, (CH₂)₆ --S--(CH₂)₈, (CH₂)₆ --S--(CH₂)₉, (CH₂)₆--S--(CH₂)₁₀, (CH₂)₆ --S--(CH₂)₁₁, (CH₂)₆ --S--(CH₂)₁₂, (CH₂)₆--S--(CH₂)₁₃, (CH₂)₈ --S--CH₂, (CH₂)₈ --S--(CH₂)₂, (CH₂)₈ --S--(CH₂)₃,(CH₂)₈ --S--(CH₂)₄, (CH₂)₈ --S--(CH₂)₅, (CH₂)₈ --S--(CH₂)₆, (CH₂)₈--S--(CH₂)₇, (CH₂)₈ --S--(CH₂)₈, (CH₂)₈ --S--(CH₂)₉, (CH₂)₈--S--(CH₂)₁₀, (CH₂)₈ --S--(CH₂)₁₁, (CH₂)₁₀ --S--CH₂, (CH₂)₁₀--S--(CH₂)₂, (CH₂)₁₀ --S--(CH₂)₃, (CH₂)₁₀ --S--(CH₂)₄, (CH₂)₁₀--S--(CH₂)₅, (CH₂)₁₀ --S--(CH₂)₆, (CH₂)₁₀ --S--(CH₂)₇, (CH₂)₁₀--S--(CH₂)₈, (CH₂)₁₀ --S--(CH₂)₉, (CH₂)₁₂ --S--CH₂, (CH₂)₁₂ --S--(CH₂)₂,(CH₂)₁₂ --S--(CH₂)₃, (CH₂)₁₂ --S--(CH₂)₄, (CH₂)₁₂ --S--(CH₂)₅, (CH₂)₁₂--S--(CH₂)₆, or (CH₂)₁₂ --S--(CH₂)₇. .Iaddend..Iadd.39. A proteincompound according to claim 33, wherein W is a divalent radical of theformula (CH₂)₂ --N(CH₃)--(CH₂)₇, (CH₂)₂ --N(CH₃)--(CH₂)₈, (CH₂)₂--N(CH₃)--(CH₂)₉, (CH₂)₂ --N(CH₃)--(CH₂)₁₀, (CH₂)₂ --N(CH₃)--(CH₂)₁₁,(CH₂)₂ --N(CH₃)--(CH₂)₁₂, (CH₂)₂ --N(CH₃)--(CH₂)₁₃, (CH₂)₂--N(CH₃)--(CH₂)₁₄, (CH₂)₂ --N(CH₃)--(CH₂)₁₅, (CH₂)₂ --N(CH₃)--(CH₂)₁₆,(CH₂)₂ --N(CH₃)--(CH₂)₁₇, (CH₂)₄ --N(CH₃)--(CH₂)₅, (CH₂)₄--N(CH₃)--(CH₂)₆, (CH₂)₄ --N(CH₃)--(CH₂)₇, (CH₂)₄ --N(CH₃)--(CH₂)₈,(CH₂)₄ --N(CH₃)--(CH₂)₉, (CH₂)₄ --N(CH₃)--(CH₂)₁₀, (CH₂)₄--N(CH₃)--(CH₂)₁₁, (CH₂)₄ --N(CH₃)--(CH₂)₁₂, (CH₂)₄ --N(CH₃)--(CH₂)₁₃,(CH₂)₄ --N(CH₃)--(CH₂)₁₄, (CH₂)₄ --N(CH₃)--(CH₂)₁₅, (CH₂)₆--N(CH₃)--(CH₂)₃, (CH₂)₆ --N(CH₃)--(CH₂)₄, (CH₂)₆ --N(CH₃)--(CH₂)₅,(CH₂)₆ --N(CH₃)--(CH₂)₆, (CH₂)₆ --N(CH₃)--(CH₂)₇, (CH₂)₆--N(CH₃)--(CH₂)₈, (CH₂)₆ --N(CH₃)--(CH₂)₉, (CH₂)₆ --N(CH₃)--(CH₂)₁₀,(CH₂)₆ --N(CH₃)--(CH₂)₁₁, (CH₂)₆ --N(CH₃)--(CH₂)₁₂, (CH₂)₆--N(CH₃)--(CH₂)₁₃, (CH₂)₂ --N(C₂ H₅)--(CH₂)₇, (CH₂)₂ --N(C₂ H₅)--(CH₂)₈,(CH₂)₂ --N(C₂ H₅)--(CH₂)₉, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₀, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₁, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₂, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₃,(CH₂)₂ --N(C₂ H₅)--(CH₂)₁₄, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₅, (CH₂)₂ --N(C₂H₅)--(CH₂)₁₆, (CH₂)₂ --N(C₂ H₅)--(CH₂)₁₇, (CH₂)₄ --N(C₂ H₅)--(CH₂)₅,(CH₂)₄ --N(C₂ H₅)--(CH₂)₆, (CH₂)₄ --N(C₂ H₅)--(CH₂)₇, (CH₂)₄ --N(C₂H₅)--(CH₂)₈, (CH₂)₄ --N(C₂ H₅)--(CH₂)₉, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₀,(CH₂)₄ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₂, (CH₂)₄ --N(C₂H₅)--(CH₂)₁₃, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₄, (CH₂)₄ --N(C₂ H₅)--(CH₂)₁₅,(CH₂)₆ --N(C₂ H₅)--(CH₂)₃, (CH₂)₆ --N(C₂ H₅)--(CH₂)₄, (CH₂)₆ --N(C₂H₅)--(CH₂)₅, (CH₂)₆ --N(C₂ H₅)--(CH₂)₆, (CH₂)₆ --N(C₂ H₅)--(CH₂)₇,(CH₂)₆ --N(C₂ H₅)--(CH₂)₈, (CH₂)₆ --N(C₂ H₅)--(CH₂)₉, (CH₂)₆ --N(C₂H₅)--(CH₂)₁₀, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₁, (CH₂)₆ --N(C₂ H₅)--(CH₂)₁₂, or(CH₂)₆ --N(C₂ H₅)--(CH₂)₁₃. .Iaddend..Iadd.40. A protein compoundaccording to claim 33, wherein W is a divalent radical of the formula(CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₅, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₇, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₉, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₁, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₂, (CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₁₃, (CH₂)₂--O--(CH₂)₂ --O--(CH₂)₁₄, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₂, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₃, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₄, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₅, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₆, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₇, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₈, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₉, (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₀, (CH₂)₄--O--(CH₂)₂ --O--(CH₂)₁₁, or (CH₂)₄ --O--(CH₂)₂ --O--(CH₂)₁₂..Iaddend..Iadd.41. A protein compound according to claim 33, wherein Wis a divalent radical of the formula (CH₂)₂ --S--S--(CH₂)₇, (CH₂)₂--S--S--(CH₂)₉, (CH₂)₂ --S--S--(CH₂)₁₁, (CH₂)₂ --S--S--(CH₂)₁₃, (CH₂)₂--S--S--(CH₂)₁₅, (CH₂)₄ --S--S--(CH₂)₅, (CH₂)₄ --S--S--(CH₂)₇, (CH₂)₄--S--S--(CH₂)₉, (CH₂)₄ --S--S--(CH₂)₁₁, (CH₂)₄ --S--S--(CH₂)₁₃, (CH₂)₆--S--S--(CH₂)₃, (CH₂)₆ --S--S--(CH₂)₅, (CH₂)₆ --S--S--(CH₂)₇, (CH₂)₆--S--S--(CH₂)₉, (CH₂)₆ --S--S--(CH₂)₁₁, (CH₂)₈ --S--S--CH₂, (CH₂)₈--S--S--(CH₂)₃, (CH₂)₈ --S--S--(CH₂)₅, (CH₂)₈ --S--S--(CH₂)₇, or (CH₂)₈--S--S--(CH₂)₉. .Iaddend..Iadd.42. A protein compound according to claim32 wherein said pharmacologically active protein is asparaginasearginase, interleukin-1, interleukin-2, interleukin-3, interleukin-4,interleukin-5, interleukin-6, interleukin-7, interleukin-8, urokinase,prourokinase, streptokinase, tissue plasminogen activator,β-glucosidase, β-glucuronidase, α-galactosidase deaminase, uricase,superoxide dismutase, insulin, bilirubin oxidase, granolocytecolony-stimulating factor, granolocyte macrophage colony-stimulatingfactor, macrophage colony-stimulating factor, neocarzinostatin,catalase, elastase, erythropoietin, interferon-α, interferon-β,interferon-γ, tumor necrosis factor-α, tumor necrosis factor-β, nervegrowth factor, epidermal growth factor, ovalbumin, platelet derivedgrowth factor, thrombomodulin, α antitrypsin, bone morphogeneticprotein, cartilage derived factor, fibroblast growth factor, growthhormone, transforming growth factor-β, blood coagulation factor IX,protein C, protein S, insulin-like growth factor, calcitonin,somatostatin, tissue inhibitor of metalloproteinase, atrial natriuretichormone, CD-4 protein cystatin, calpastatin, urinastatin or parathyroidhormone. .Iaddend..Iadd.43. A protein compound according to claim 42,wherein W is a divalent radical of the formula (CH₂)₁₂, (CH₂)₁₄,(CH₂)₁₆, (CH₂)₁₈ or (CH₂)₂₀. .Iaddend..Iadd.44. A protein compoundaccording to claim 43, wherein said pharmacologically active protein issuperoxide dismutase. .Iaddend..Iadd.45. A protein compound according toclaim 44, wherein W is (CH₂)₁₂. .Iaddend..Iadd.46. The protein compoundaccording to claim 45, wherein n is 3.6. .Iaddend..Iadd.47. The proteincompound according to claim 45, wherein n is 4.4. .Iaddend..Iadd.48. Theprotein compound according to claim 45, wherein n is 5.4..Iaddend..Iadd.49. A protein compound according to claim 44, wherein Wis (CH₂)₁₆. .Iaddend..Iadd.50. The protein compound according to claim49, wherein n is 2.0. .Iaddend..Iadd.51. A protein compound according toclaim 44, wherein W is (CH₂)₁₈. .Iaddend..Iadd.52. The protein compoundaccording to claim 51, wherein n is 2.0. .Iaddend..Iadd.53. A proteincompound according to claim 43, wherein said pharmacologically activeprotein is neocarzinostatin. .Iaddend..Iadd.54. A protein compoundaccording to claim 53, wherein W is (CH₂)₁₄. .Iaddend..Iadd.55. Theprotein compound according to claim 54, having no free amino groups..Iaddend..Iadd.56. A protein compound according to claim 53, wherein Wis (CH₂)₁₆. .Iaddend..Iadd.57. The protein compound according to claim56, having no free amino groups. .Iaddend..Iadd.58. A process forpreparing a protein compound having the formula

    (protein)(Z).sub.n

wherein (protein) represents a pharmacologically active protein having namino radicals each derivable from an amino group by removal of one ofits hydrogen atoms, and (Z) is a radical of a long chain carboxylic acidhaving the formula ##STR24## wherein W is a divalent long chainhydrocarbon radical which is uninterrupted or interrupted by one or moregroups each independently selected from the group consisting of anoxygen atom, a sulfur atom and a --N(R¹) group wherein R¹ is loweralkyl, said radical W having from 8 to 28 principal chain atoms, each(Z) being derivable from a long-chain dicarboxylic acid HO₂ C--W--CO₂ Hby removal of a hydroxyl group from one of its carbonyl groups, each (Z)being bonded to one of said n amino radicals in said protein, n being anaverage of the number of amide bonds between (Z) and (protein) and beinga number from 1 to 8, said process comprising reacting a compound of theformula: ##STR25## or a salt thereof, wherein W is defined as above and##STR26## is a radical of the formula ##STR27## wherein each of R², R³,R⁴ and R⁵, which are the same or different, is a hydrogen atom; an alkylradical; an aryl radical; an aralkyl radical; an --SO₃ H group; aradical of the formula --OR⁶ wherein R⁶ is selected from the groupconsisting of a hydrogen atom, an alkyl radical, an aryl radical, anaralkyl radical and an acyl radical; a radical of the formula --NR⁷ R⁸wherein each of R⁷ and R⁸, which are the same or different, is selectedfrom the group consisting of an alkyl radical, an aryl radical, anaralkyl radical and an acyl radical; or a radical of the formula --CO₂R⁹ wherein R⁹ is selected from the group consisting of a hydrogen atom,an alkyl radical, an aryl radical and an aralkyl radical; or R², R³, R⁴and R⁵ in combination with the carbon atoms to which they bond, form abenzene, cyclohexane, cyclopentane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hepta-2-ene, 7-oxabicyclo[2.2.1]heptane or7-oxabicyclo[2.2.1]hepta-2-ene ring system which is unsubstituted orsubstituted by --SO₃ H, --CO₂ H, --OH, F, Cl, Br, I, --CH₃ or --OCH₃ ;or R² and R³, R⁴ and R⁵, or both, in combination, are a methylene orisopropylidene group; and each of R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, whichare the same or different, is a hydrogen atom; an alkyl radical; an arylradical; an aralkyl radical; an --SO₃ H group; a radical of the formula--OR⁶ wherein R⁶ is selected from the group consisting of a hydrogenatom, an alkyl radical; an aryl radical, an aralkyl radical and an acylradical; a radical of the formula --NR⁷ R⁸ wherein each of R⁷ and R⁸,which are the same or different, is selected from the group consistingof an alkyl radical, an aryl radical, an aralkyl radical and an arylradical; or a radical of the formula --CO₂ R⁹ wherein R⁹ is selectedfrom the group consisting of a hydrogen atom, an alkyl radical, an arylradical or an aralkyl radical; with a pharmaceutically active proteindefined as above in an aqueous solution at a pH maintained within therange of 6 to 10, at a reaction temperature of from about 3° to 50° C.which does not exceed the denaturation temperature of the protein;followed by separating the resultant protein compound from the reactionmedium. .Iaddend..Iadd.59. A process according to claim 58, wherein thepharmacologically active protein starting material is asparaginase,arginase, interleukin-1, interleukin-2, interleukin-3, interleukin-4,interleukin-5, interleukin-6, interleukin-7, interleukin-8, urokinase,prourokinase, streptokinase, tissue plasminogen activator,β-glucosidase, β-glucuronidase, α-galactosidase, adenosine deaminase,uricase, superoxide dismutase, insulin, bilirubin oxidase, granolocytecolony-stimulating factor, granolocyte macrophage colony-stimulatingfactor, macrophage colony-stimulating factor, neocarzinostatin,catalase, elastase, erythropoietin, interferon-α, interferon-β,interferon-γ, tumor necrosis factor-α, tumor necrosis factor-β, nervegrowth factor, epidermal growth factor, ovalbumin, platelet derivedgrowth factor, thrombomodulin, α-antitrypsin, bone morphogeneticprotein, cartilage derived factor, fibroblast growth factor, growthhormone, transforming growth factor-β, blood coagulation factor IX,protein C, protein S, insulin-like growth factor, calcitonin,somatostatin, tissue inhibitor of metalloproteinase, atrial natriuretichormone, CD-4 protein, cystatin, calpastatin, urinastatin or parathyroidhormone. .Iaddend..Iadd.60. A process according to claim 58, wherein thestarting material of formula (II)is:N-(13-carboxytridecanoyloxy)succinimide;N-(15-carboxypentadecanoyloxy)succinimide;N-(17-carboxyheptadecanoyloxy)succinimide;N-(19-carboxynonadecanoyloxy)succinimide;N-(21-carboxyheneicosanoyloxy)succinimide;N-(15-carboxypentadecanoyloxy)phthalimide;N-(15-carboxypentadecanoyloxy)tetramethylphthalimide;N-(15-carboxypentadecanoyloxy)5-norbornene-2,3-dicarboximide;N-(15-carboxypentadecanoyloxy)tartrimide;N-(13-carboxytridecanoyloxy)sulfosuccinimide sodium salt;N-(15-carboxypentadecanoyloxy)-3-isopropylsuccinimide;N-(15-carboxypentadecanoyloxy)tetramethylsuccinimide;N-(15-carboxypentadecanoyloxy)-3-benzylsuccinimide;N-(15-carboxypentadecanoyloxy)itaconimide; orN-(15-carboxypentadecanoyloxy)glutarimide. .Iaddend..Iadd.61. A processaccording to claim 59, wherein the starting material of formula (II)is:N-(13-carboxytridecanoyloxy)succinimide;N-(15-carboxypentadecanoyloxy)succinimide;N-(17-carboxyheptadecanoyloxy)succinimide;N-(19-carboxynonadecanoyloxy)succinimide;N-(21-carboxyheneicosanoyloxy)succinimide;N-(15-carboxypentadecanoyloxy)phthalimide;N-(15-carboxypentadecanoyloxy)tetramethylphthalimide;N-(15-carboxypentadecanoyloxy)5-norbornene-2,3-dicarboximide;N-(15-carboxypentadecanoyloxy)tartrimide;N-(13-carboxytridecanoyloxy)sulfosuccinimide sodium salt;N-(15-carboxypentadecanoyloxy)-3-isopropylsuccinimide;N-(15-carboxypentadecanoyloxy)tetramethylsuccinimide;N-(15-carboxypentadecanoyloxy)-3-benzylsuccinimide;N-(15-carboxypentadecanoyloxy)itaconimide; orN-(15-carboxypentadecanoyloxy)glutarimide. .Iaddend..Iadd.62. A processaccording to claim 61, wherein the pharmacologically active proteinstarting material is superoxide dismutase and the starting material offormula (II) is N-(13-carboxytridecanoyloxy)succinimide..Iaddend..Iadd.63. A compound according to claim 61, wherein thepharmacologically active protein starting material is superoxidedismutase and the starting material of formula (II) isN-(17-carboxyheptadecanoyloxy)succinimide. .Iaddend..Iadd.64. A processaccording to claim 61, wherein the pharmacologically active proteinstarting material is superoxide dismutase and the starting material offormula (II) is N-(19-carboxynonadecanoyloxy)succinimide..Iaddend..Iadd.65. A process according to claim 61, wherein thepharmacologically active protein starting material is neocarzinostatinand the starting material of formula (II) isN-(15-carboxypentadecanoyloxy)succinimide. .Iaddend..Iadd.66. A processaccording to claim 61, wherein the pharmacologically active proteinstarting material is neocarzinostatin and the starting material offormula (II) is N-(17-carboxyheptadecanoyloxy)succinimide. .Iaddend.